Modulation of dopamine's effect at dopamine 2 receptors (D2R) mediated by association with the ghrelin receptor, GHSR
John B. FurnessFarhad DehkhodaEmily WhitfieldLinda J. FothergillDesye MisgenawMitchell RinguetSebastian G. B. Furness
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Abstract:
The typical action of dopamine at the dopamine 2 receptor (D2R) on CNS neurons is inhibition, an effect mediated via Gαi/o through GIRK channels. However, at two sites, autonomic preganglionic neurons in the lumbosacral spinal cord, and in the lateral hypothalamus, dopamine causes neuronal excitation through D2R. At both sites, dopamine neurons that are excited by dopamine express the ghrelin receptor, GHSR. Ghrelin is absent from the lateral hypothalamus and spinal cord, and it has been proposed that GHSR may modulate D2R signaling by the formation of heterodimers.In lumbrosacral spinal cord neurons of the defecation centre, D2R and GHSR agonists applied successively were both excitatory. Antagonism of GHSR at these neurons blocked the excitatory effect of DR2 stimulation, which was also blocked by depletion of intracellular calcium (iCa2+). We further investigated this interaction in recombinant cultured cells. In CHO cells expressing D2R, dopamine agonists had almost no effect on iCa2+, whereas in the presence of GHSR, D2R coupling to iCa2+ was observed in response to nanomolar dopamine. The elevation of iCa2+ by dopamine in D2R/GHSR cells was reduced by either D2R or GHSR antagonism, but the effect of a GHSR agonist was reduced only by GHSR antagonism. D2R coupling to iCa2+ in the presence of GHSR was dependent on both Gαq and Gαi/o, whereas ghrelin agonist coupling was dependent only on Gαq. D2R mediated effects on cAMP were dependent only on Gαi/o and were not effected by GHSR antagonism. D2R and GHSR in the membranes of CHO cells, revealed by fluorescent ligands, moved independently when tracked at high resolution in real time and, using fluorescent lifetime imaging, individual labelled DR2 sites were not in close enough proximity to detect resonance energy transfer (no detectable FRET). Consistent with coupling being via downstream crosstalk, no detectable DR2 dependent iCa2+ was evident in cells expressing the GHSR – A204E mutant, which lacks constitutive activity. The DR2-dependent iCa2+ increase was restored in these cells using subthreshold pre-stimulation with ghrelin. In native neurons of the defecation center, inward currents in response to D2R agonism were blocked by U73122, an inhibitor of PLCβ. Together this data indicates that dopamine-mediated excitation was dependent on GHSR, PLCβ and iCa2+, in both native and recombinant cells. We conclude that co-expression of GHSR causes augmentation of agonist-induced, D2R-mediated PLCβ activation and store Ca2+ release in recombinant cells and in a population of autonomic preganglionic neurons. D2R mediated excitation in D2R/GHSR cells is both Gαi/o and Gαq/11 dependent, but does not require receptor dimerisation. Our findings reveal a novel interaction between GPCRs, in a physiologically relevant system, that does not require direct receptor interaction and has broad implications for recoding of metabotropic neurotransmitter responses via modulation through other GPCRs. NHMRC grant, APP2012657, to SGBF This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.Keywords:
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A 20-mer phosphorothioate oligodeoxynucleotide (D2 antisense) to the D2 antisense dopamine receptor messenger RNA (mRNA) was administered i.c.v. to mice with unilateral 6-hydroxydopamine lesions of the corpus striatum. The mice were then challenged with acute injections of various agents that cause contralateral rotational behavior, and the levels of D1 and D2 dopamine receptors and their respective mRNAs were determined in the corpus striatum. Administering the D2 antisense inhibited rotations induced by the D2 dopamine receptor agonists quinpirole and N-propyl-N-2-thienylethylamine-5-hydroxytetralin but did not block rotations induced by the D1 dopamine receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol HCl or by the muscarinic cholinergic receptor agonist oxotremorine. The reduction in quinpirole-induced rotational behavior was related to the amount and length of time the D2 antisense was given. Significant reductions in behavior were seen within 1 day of repeated injections of D2 antisense, and almost complete inhibition was seen after 6 days of treatment. Recovery from inhibition occurred by 2 days after cessation of antisense treatment. Repeated treatment with D2 antisense significantly reduced the levels of D2 dopamine receptors and D2 dopamine receptor mRNA, but not the levels of D1 receptors or D1 mRNA, in the dorsolateral area of the lesioned striatum. Treatment with an oligodeoxynucleotide with randomly placed nucleotides did not inhibit quinpirole-induced rotations or alter D2 dopamine receptors or D2 dopamine receptor mRNA in either area of striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
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