ChenWei Lee

Harvard University

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Arthur C. Waltman

Harvard University Press

Glenn M. LaMuraglia

Massachusetts General Hospital

Stuart C. Geller

Massachusetts General Hospital

Thomas J. Gardella

Harvard University

William M. Abbott

Trinity College Dublin

Ming‐Hui Fan

Sichuan University

Jonathan P. Gertler

Massachusetts General Hospital

Richard P. Cambria

University of Maryland, Baltimore

David C. Brewster

Harvard University

Chieh-Min Fan

Far Eastern Memorial Hospital

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Harvard University

Massachusetts General Hospital

Harvard University Press

Boston University

University of Maryland, Baltimore

Boston Medical Center

University Medical Center

University of Michigan–Ann Arbor

Massachusetts Eye and Ear Infirmary

Duke Medical Center

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Transmembrane Residues of the Parathyroid Hormone (PTH)/PTH-related Peptide Receptor That Specifically Affect Binding and Signaling by Agonist Ligands

Journal of Biological Chemistry (1996)

Thomas J. Gardella Michael D. Luck Ming‐Hui Fan ChenWei Lee

Polar residues within the transmembrane domains (TMs) of G protein-coupled receptors have been implicated to be important determinants of receptor function. We have identified mutations at two polar sites in the TM regions of the rat parathyroid hormone (PTH)/PTH-related peptide receptor, Arg-233 in TM 2 and Gln-451 in TM 7, that caused 17-200-fold reductions in the binding affinity of the agonist peptide PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) without affecting the binding affinity of the antagonist/partial agonist PTH-(3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar). When mutations at the TM 2 and TM 7 sites were combined, binding affinity for PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) was restored to nearly that of the wild type receptor. The double mutant receptors, however, were completely defective in signaling cAMP or inositol phosphate production in response to PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) agonist ligand. The results demonstrate that Arg-233 and Gln-451 have important roles in determining agonist binding affinity and transmembrane signaling. Furthermore, the finding that residues in TM 2 and TM 7 are functionally linked suggests that the TM domain topology of the PTH/PTH-related peptide receptor may resemble that of receptors in the rhodopsin/β-adrenergic receptor family, for which structural and mutagenesis data suggest interactions between TMs 2 and 7. Polar residues within the transmembrane domains (TMs) of G protein-coupled receptors have been implicated to be important determinants of receptor function. We have identified mutations at two polar sites in the TM regions of the rat parathyroid hormone (PTH)/PTH-related peptide receptor, Arg-233 in TM 2 and Gln-451 in TM 7, that caused 17-200-fold reductions in the binding affinity of the agonist peptide PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) without affecting the binding affinity of the antagonist/partial agonist PTH-(3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar). When mutations at the TM 2 and TM 7 sites were combined, binding affinity for PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) was restored to nearly that of the wild type receptor. The double mutant receptors, however, were completely defective in signaling cAMP or inositol phosphate production in response to PTH-(1Jüppner H. Abou-Samra A.-B. Freeman M. Kong X.-F. Schipani E. Richards J. Kolakowski Jr., L.F. Hock J. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Science. 1991; 254: 1024-1026Crossref PubMed Scopus (1120) Google Scholar, 2Abou-Samra A.B. Jüppner H. Force T. Freeman M. Kong X.F. Schipani E. Urena P. Richards J. Bonventre J.V. Potts Jr., J.T. Kronenberg H.M. Segre G.V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2732-2736Crossref PubMed Scopus (984) Google Scholar, 3Jüppner H. Schipani E. Bringhurst F.R. McClure I. Keutmann H.T. Potts Jr, Kronenberg H.M. Abou-Samra A.B. Segre G.V. Gardella T. Endocrinology. 1994; 134: 879-884Crossref PubMed Scopus (118) Google Scholar, 4Lee C. Gardella T. Abou-Samra A.-B. Nussbaum S. Segre G. Potts J. Kronenberg H. Juppner H. Endocrinology. 1994; 135: 1488-1495Crossref PubMed Scopus (113) Google Scholar, 5Gardella T.J. Jüppner H. Wilson A.K. Keutmann H.T. Abou-Samra A.B. Segre G.V. Bringhurst F.R. Potts J.T. Nussbaum S.R. Kronenberg H.M. Endocrinology. 1994; 135: 1186-1194Crossref PubMed Scopus (70) Google Scholar, 6Holtmann M. Hadac E. Miller L. J. Biol. Chem. 1995; 270: 14394-14398Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 7Stroop S. Kuestner R. Serwold T. Chen L. Moore E. Biochemistry. 1994; 34: 1050-1057Crossref Scopus (92) Google Scholar, 8Buggy J.J. Livingston J.N. Rabin D.U. Yoo-Warren H. J. Biol. Chem. 1995; 270: 7474-7478Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Baldwin J. EMBO J. 1993; 12: 1693-1703Crossref PubMed Scopus (875) Google Scholar, 10Strader C.D. Sigal I.S. Register R.B. Candelore M.R. Rands E. Dixon R.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 4384-4388Crossref PubMed Scopus (344) Google Scholar, 11Strader C.D. Gaffney T. Sugg E.E. Candelore M.R. Keys R. Patchett A.A. Dixon R.A. J. Biol. Chem. 1991; 266: 5-8Abstract Full Text PDF PubMed Google Scholar, 12Huang R. Yu H. Strader C. Fong T. Biochemistry. 1994; 33: 3007-3013Crossref PubMed Scopus (134) Google Scholar, 13Rosenkilde M.M. Cahir M. Gether U. Hjorth S.A. Schwartz T.W. J. Biol. Chem. 1994; 269: 28160-28164Abstract Full Text PDF PubMed Google Scholar, 14Krystek Jr., S.R. Patel P. Rose P. Fisher S. Kienzle B. Lach D. Liu E. Lynch J. Novotny J. Webb M. J. Biol. Chem. 1994; 269: 12383-12386Abstract Full Text PDF PubMed Google Scholar, 15Lee J. Elliott J. Sutiphong J. Friesen W. Ohlstein E. Stadel J. Gleason J. Peishoff C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7164-7168Crossref PubMed Scopus (38) Google Scholar, 16Hunyady L. Bor M. Balla T. Catt K. J. Biol. Chem. 1995; 270: 9702-9705Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 17Ji I. Ji T. J. Biol. Chem. 1991; 266: 14953-14957Abstract Full Text PDF PubMed Google Scholar, 18Henderson R. Balswin J.M. Ceska T.A. Zemlin F. Beckman E. Downing K.H. J. Mol. Biol. 1990; 213: 899-929Crossref PubMed Scopus (2500) Google Scholar, 19Schertler G. Villa C. Henderson R. Nature. 1995; 362: 770-772Crossref Scopus (704) Google Scholar, 20Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1992; 267: 21991-21994Abstract Full Text PDF PubMed Google Scholar, 21Sealfon S. Chi L. Ebersole B. Rodic V. Zhang D. Ballesteros J. Weinstein H. Mol. Pharmacol. 1995; 270: 16683-16688Google Scholar, 22Zhou W. Flanagan C. Ballesteros J. Konvicka K. Davidson J. Weinstein H. Millar R. Sealfon S. Mol. Pharmacol. 1994; 45: 165-170PubMed Google Scholar, 23Mizobe T. Maze M. Lam V. Suryanarayana S. von Zastrow M. Kobilka B.K. J. Biol. Chem. 1996; 271: 2387-2389Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 24Kolodziej P.A. Young R.A. Methods Enzymol. 1991; 194: 508-519Crossref PubMed Scopus (423) Google Scholar, 25Kunkel T.A. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 488-492Crossref PubMed Scopus (4878) Google Scholar, 26Seed B. Aruffo A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3365-3369Crossref PubMed Scopus (787) Google Scholar, 27Lee C. Luck M. Juppner H. Potts J. Kronenberg H. Gardella T. Mol. Endocrinol. 1995; 9: 1269-1278Crossref PubMed Google Scholar, 28Berridge M. Dawson R. Downes C. Heslop J. Irvine R. Biochem. J. 1983; 212: 473-482Crossref PubMed Scopus (1537) Google Scholar, 29Iida-Klein A. Guo J. Xie L. Jüppner H. Potts Jr., J.T. Kronenberg H.M. Bringhurst F. Abou-Samra A.B. Segre G.V. J. Biol. Chem. 1995; 270: 8458-8465Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 30Goltzman D. Peytremann A. Callahan E. Tregear G.W. Potts Jr., J.T. J. Biol. Chem. 1975; 250: 3199-3203Abstract Full Text PDF PubMed Google Scholar, 31Rost B. Casadio R. Fariselli P. Sander C. Prot. Sci. 1995; 4: 521-533Crossref PubMed Scopus (640) Google Scholar, 32De Lean A. Stadel J. Lefkowitz R. J. Biol. Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 33Samama P. Cotecchia S. Costa T. Lefkowitz R. J. Biol. Chem. 1993; 268: 4625-4636Abstract Full Text PDF PubMed Google Scholar, 34Mayo K.E. Mol. Endocrinol. 1992; 6: 1734-1744Crossref PubMed Scopus (221) Google Scholar) agonist ligand. The results demonstrate that Arg-233 and Gln-451 have important roles in determining agonist binding affinity and transmembrane signaling. Furthermore, the finding that residues in TM 2 and TM 7 are functionally linked suggests that the TM domain topology of the PTH/PTH-related peptide receptor may resemble that of receptors in the rhodopsin/β-adrenergic receptor family, for which structural and mutagenesis data suggest interactions between TMs 2 and 7.

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