Somatostatin receptors in endocrine tumors
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Most neuroendocrine tumors express receptors for somatostatin which was originally isolated as a hormone with growth hormone releasing inhibiting potential. The molecular cloning of five receptor subtypes for somatostatin has expanded our knowledge on the actions of this peptide. We studied the expression of all five somatostatin receptor subtypes in various normal human tissues and a variety of endocrine tumors. Different quantitative expression rates in normal tissues were identified by realtime RT-PCR. Expression in these tissues was confirmed by immunohistochemical analysis. We then compared the physiological expression to the somatostatin receptor expression in tumors arising from the same tissue. Our investigation of pituitary adenomas revealed that somatostatin receptor subtypes are not only expressed in GH-producing adenomas but also in ACTH-producing adenomas and prolactinomas as well as in non-functioning pituitary adenomas. Further analysis of other endocrine tumors demonstrated expression in pheochromocytomas as well as in tumors of the adrenal cortex with tumor-specific distribution pattern. This may offer new diagnostic and therapeutic possibilities with multiligand or subtype specific somatostatin analogs. Somatostatin analogues are very effective in the treatment of symptoms related to endocrine tumors. New analogues like the multi-ligand SOM230 are currently studied in phase 2 studies. The high expression of somatostatin receptors is used to localize endocrine tumors by receptor szintigraphy with radiolabeled somatostatin analogues. Tumor-targeted radioactive treatment based on somatostatin analogues is currently evaluated as a treatment option.Keywords:
Somatostatin receptor 1
Somatostatin receptor 3
Pituitary Tumors
목적: 통각의 전달 과정에는 몇 가지 신경 전달물질이 중요하게 작용하는 것으로 알려져 있다. 그 중 somatostatin과 관련된 통각의 조절에 대한 기전 연구를 위해서는 somatostatin이 직접적으로 결합하는 somatostatin 수용기(sstr)에 대한 연구가 필수 불가결하다. 특히 sstr중에서 sstr2가 통각 조절에 매우 중요하므로, 본 연구에서는 신경원성 통증의 조절과 관련된 somatostatin과 sstr2에 대한 면역 반응성을 관찰하고자 하였다. 대상 및 방법: 10마리의 쥐(Sprague-Dawley 랫드 후지, 수컷, 체중 200-250g)를 대상으로 제 4-6 요수분절에 해당하는 척수 신경절(dorsal root ganglia, DRG)을 적출한 다음 sstr2 (sstr2A, sstr2B)에 대한 면역 조직학적 염색을 실시하였다. 결과: 척수에서 sstr2의 isoforms인 sstr2A와 sstr2B의 면역 반응이 척수 후각에서 서로 상이한 분포를 보였는데, sstr2A의 면역 반응성은 somatostatin의 분포와 일치하는 천층인 제 Ⅰ, Ⅱ층에서 관찰된 반면에, sstr2B의 경우는 주로 제 Ⅲ-Ⅵ층에서 관찰되었다. 척수 신경절에서 sstr2A와 sstr2B의 면역 반응은 제 4-6 요수분절 척수 신경절 내에서 주로 중간 크기의 신경절 세포들에서 강하게 나타났으며, 일부 큰 크기와 작은 크기의 신경절 세포에서도 면역 반응이 관찰되었다. 결론: 척수 신경절을 통한 통증 전달의 완화 기능을 담당히는 것들 중 하나인 somatostatin은 척수 후각에서 somatostatin receptors 중 sstr2A의 분포는 somatostatin의 분포와 일치하나, sstr2B는 somatostatin과 다르게 분포하는 것으로 보아 척수에서 somatostatin의 기능에 또 다른 조절을 할 것으로 생각된다. 이런 면에서 생각해 볼 때 통증 조절시 수용기의 종류에 따라 그 역할이 매우 다양할 것이므로, 임상 적용시 많은 신경 활성 물질들의 수용기에 대한 선행 연구가 반드시 필요하다다고 사료된다.
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Somatostatin-14 and somatostatin-28 are derived from the same peptide, prosomatostatin by the post-translational modification and make a somatostatin family. Recent advance in molecular biology has revealed that somatostatin receptors also constitute a family of structurally-related proteins. The members of the somatostatin receptor family are SSTR1-5, which have different expression pattern, pharmacological characterization and coupling with intracellular second messenger systems. Efficacy of SMS 201-995, a clinically available somatostatin analog, against endocrine tumors seems to be correlated with expression of SSTR2 which has a high affinity for SMS 201-995. Cloning of somatostatin receptors will further facilitate development and application of somatostatin analogs in diagnosis and treatment of tumors.
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The five known somatostatin receptors serve unique biological roles by virtue of their tissue-specific expression and particular biochemical properties. However, the function of any individual receptor in its normal physiological milieu is not understood. Studies to address this problem have been difficult because tissues and cell lines often express multiple somatostatin receptors and, in the absence of receptor-selective somatostatin analogues, the actions of individual receptors cannot be identified. Moreover, the biological and biochemical actions of somatostatin receptors depend on their cellular environment, so that the behaviour of a receptor expressed in heterologous cells does not necessarily mimic that of endogenous receptors. We have developed two approaches to examine somatostatin receptors which circumvent these problems. Using a biotinylated somatostatin analogue for affinity purification, we isolated somatostatin receptors together with associated G proteins. Subsequent analysis of the purified complex with G protein-specific antibodies showed that the somatostatin receptors in AR42J cells preferentially couple with two pertussis toxin-sensitive G proteins: Giα1 and Giα3. To examine individual receptor types, we developed receptor-specific antibodies and used them to show that both sstrl and sstr2 proteins were present in the GH4C1 pituitary cell line whereas AR42J cells contained sstr2 but not sstr1. Immunoprecipitation of receptor-G protein complexes from GH4C1 cells showed that sstr1 and sstr2 are both coupled to pertussis toxin-sensitive G proteins, in contrast to the results observed when these receptors are overexpressed in some non-endocrine cells. We also showed that the somatostatin receptors in GH4C1 cells are subject to both homologous and heterologous hormonal regulation. The mechanisms involved in the regulation of different receptor types are now being characterized using the receptor-specific antibodies to isolate the individual receptor proteins. Elucidating signal transduction by endogenous somatostatin receptors as well as their hormonal regulation will be critical for understanding the functions of these receptors in the different physiological targets of somatostatin.
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Abstract Somatostatin is a peptide hormone regulating endocrine systems through binding to G-protein-coupled somatostatin receptors. somatostatin receptor 2 (SSTR2) is one of the human somatostatin receptors and highly implicated in cancers and neurological disorders. Here, we report the high resolution cryo-EM structure of full-length human SSTR2 bound to the agonist somatostatin (SST-14) complex with inhibitory G (G i ) proteins. Our structure shows that seven transmembrane helices form a deep pocket for ligand binding and that the highly conserved Trp-Lys motif of SST-14 positions at the bottom of the pocket. Furthermore, our sequence analysis combined with AlphaFold modeled structures of other SSTR isoforms provide how SSTR family proteins specifically interact with their cognate ligands. This work provides the first glimpse into the molecular recognition of somatostatin receptor and crucial resource to develop therapeutics targeting somatostatin receptors.
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Regulation of tyrosine phosphorylation is thought to be an essential step in signal transduction mechanisms that mediate cellular responses. In pancreatic tumour cells we demonstrated that somatostatin analogues inhibited cell proliferation and stimulated a membrane protein tyrosine phosphatase (PTP) activity at concentrations at which they bind to the somatostatin receptor. To elucidate the role of PTP in the signal transduction pathway activated by somatostatin receptors we first studied the interaction of PTP with the somatostatin receptor at the membrane. We purified somatostatin receptors by immunoaffinity from pancreatic membranes that strongly expressed the type 2 somatostatin receptor sstr2. We identified the receptor as an 87 kDa protein. We demonstrated that a PTP activity co-purified with somatostatin receptors. The PTP was identified as a 66 kDa protein immunoreactive to antibodies against SHPTP1. These antibodies immunoprecipitated somatostatin receptors either occupied or unoccupied by ligand indicating that SHPTP1 is associated with somatostatin receptors. We then expressed sstr2A in monkey kidney COS-7 cells and mouse NIH/3T3 fibroblasts and demonstrated that somatostatin analogues (RC 160, octreotide and BIM 23014) which exhibited high affinity for sstr2 stimulated a PTP activity and inhibited cell proliferation in proportion to their affinities for sstr2. Under the same conditions these analogues have no effect on the growth of cells expressing sstr1. All these results suggest that a PTP related to SHPTP1 is associated with somatostatin receptors and may be involved in the negative growth signal promoted by sstr2.
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The neuropeptide somatostatin is widely distributed in the central nervous system and in peripheral tissues and may be involved in the regulation of a number of physiological functions including movement and cognition. Somatostatin may also have a role in the development of the central nervous system, in particular, the cerebellum and spinal cord. Somatostatin induces its actions by interacting with a family of membrane associated receptors. Recently, five somatostatin receptors have been cloned and referred to as SSTR1-SSTR5. The distribution of the expression of the mRNAs for these receptors are distinct but overlapping. Preliminary pharmacological analysis of these receptors may lead to the development of selective ligands at these receptors. These compounds may be useful in identifying the selective functions of these receptor subtypes. Some somatostatin analogues have antiproliferative actions and are used presently to treat carcinoids. Development of subtype selective somatostatin analogues could be helpful in further identifying somatostatin receptor-expressing tumors and in the treatment of cancer. The cloning of these receptors has now opened up the possibility of more clearly investigating the functions of somatostatin in the brain and peripheral tissues and will facilitate the generation of new somatostatin drugs that may be employed for the treatment of a number of diseases.
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