Disease relevance of SSTR2

• In three cases of pheochromocytoma, SSTR1 and SSTR2 mRNAs were detected, showing an expression pattern identical to that of normal adrenal gland [1].
• Since SMS 201-995 was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, but had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, this study suggests that the efficacy of SMS 201-995 may depend, at least in part, on the expression of SSTR2 in tumors [1].
• In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied [2].
• Whereas meningiomas, neuroblastomas, pituitary adenomas, small cell lung carcinomas, lymphomas, and breast tumors expressed primarily a high abundance of SSTR2, carcinoids, islet cell carcinomas, medullary thyroid carcinomas, and ovarian tumors had a mixed distribution of the somatostatin receptor subtypes [3].
• Using reverse transcription-PCR analysis, we demonstrated the expression of SSTR2 and SSTR5 in intraprostatic tumors and their metastases in lymph nodes as well as in s.c. tumors [4].

Psychiatry related information on SSTR2

• Furthermore, MK 678, when applied to the nucleus accumbens, evokes locomotor activity, and SRIF1 receptors in this brain region selectively mediate the stimulation of this behavioral response to SRIF [5].
• After SRIF administration, total sleep time and rapid eye movement (REM) sleep decreased significantly, and more time was spent awake in the first sleep cycle, suggesting that SRIF induces sleep deterioration in the elderly [6].
• In neurodegenerative diseases, cortical SRIF concentrations are decreased in Alzheimer's and Parkinson's disease associated with dementia while SRIF-binding sites are only affected in Alzheimer's disease [7].
• Finally, the decrease in SRIF concentrations in the cerebrospinal fluid (CSF) and the central nervous system (CNS) commonly associated with Alzheimer's disease is critically evaluated [8].
• CSF SRIF concentrations in patients with anorexia nervosa, both at low weight and after weight recovery, were similar to those in controls [9].

High impact information on SSTR2

• The neuropeptide somatostatin (SRIF) has diverse physiological actions in the brain and endocrine organs [10].
• The availability of the cloned receptors will now allow for detailed structure-function analysis of SRIF receptors and will facilitate development of subtype-selective agonists and antagonists that could be useful in the treatment of central nervous system and endocrine disorders [10].
• Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified [11].
• Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4) [11].
• Four of the subtypes (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis [11].

Chemical compound and disease context of SSTR2

• The effects of GTP gamma S and pertussis toxin on [125I-Tyr11]somatostatin-14 binding indicated that SSTR2 may couple exclusively to pertussis toxin-sensitive G proteins, whereas SSTR1 may couple to both pertussis-sensitive and -insensitive G proteins [12].
• These findings suggest that SSTR2 receptors can be regulated and they associate with pertussis toxin-sensitive guanine nucleotide-binding proteins, whereas SSTR1 receptors do not [13].
• METHODS: Nonradioactive in situ hybridization was performed with specific fluorescein-labeled SSTR2 and SSTR4 riboprobes on consecutive sections of benign prostatic hyperplasia (BPH) and prostate cancer tissues [14].
• We investigated the effects of SST-14, lanreotide, and SSTR 2 (BIM-23190) and SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture [15].
• In animal models the somatostatin analog angiopeptin inhibits intimal hyperplasia by acting primarily through somatostatin receptor 2 (SSTR-2) [16].

Biological context of SSTR2

• There is 46% identity and 70% similarity between the amino acid sequences of SSTR1 and SSTR2 [17].
• Whereas growth inhibition has been reported to follow stimulation of protein tyrosine phosphatase via SSTR2 or inhibition of Ca2+ channels via SSTR5 in heterologous expression systems, the subtype selectivity for signaling apoptosis has not been investigated [18].
• On the other hand, in the nonresponder group, CT secretion was reduced by the SSTR1 selective agonist, whereas cell viability was inhibited by SSTR2 selective agonists [19].
• No association between SSTR2 genotypes and GH and IGF-I levels was found [20].
• The present study demonstrates that the human MTC cell line TT stably expresses all the SSTR subtypes and responds to SSTR2 and SSTR5 activation by subtype-selective agonists with two different patterns in terms of [(3)H]thymidine ([(3)H]thy) incorporation and cell number [21].

Anatomical context of SSTR2

• RNA blotting studies show that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively [17].
• We expressed two somatostatin receptor subtypes, SSTR1 and SSTR2, stably in mouse fibroblast Ltk- cells and transiently in human embryonic kidney HEK293 cells to investigate subtype-specific pharmacological and functional properties [12].
• We found that the previously identified SSTR1 and SSTR2 are the major subtypes expressed in this cell line [22].
• Cultured tumor cells were treated with SRIH, lanreotide (BIM-23014), or SRIH analogs selective for SSTR2 (BIM-23120), SSTR5 (BIM-23206), or SSTR1 (BIM-23926) [23].
• SSTR1 and SSTR2 immunoreactivity (-ir) was observed on a variety of cells within all analyzed tissues including cornea, iris, trabecular meshwork, Schlemm's canal, ciliary processes, ciliary muscle, retina, choroid, cultured RPE cells, and optic nerve [24].

Associations of SSTR2 with chemical compounds

• We have also found that human SSTR2 shows a high affinity for SMS 201-995, which has been used clinically for the treatment of endocrine tumors [1].
• Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs [25].
• The expression of SSTR2 and/or SSTR5 was 100%, consistent with the presence of RC-160 binding [26].
• In contrast, the SSTR2 receptor was insensitive to CGP 23996-like compounds but bound MK 678 with high affinity [13].
• SSTR2-infected tumors were visible on imaging 6 days after VV injection and could be visualized for up to 3 weeks post-viral injection using repeat injections of 111In-pentetreotide [27].
• A combined treatment of a demethylating agent, 5-aza-2-deoxycytidine and a histone deacetylase inhibitor, trichostatin A, leads to increased expression of hSSTR2 mRNA in cell lines in which the CpG island is methylated [28].

Physical interactions of SSTR2

• SRIF2 receptors are not efficiently coupled to G proteins and have a distinct but overlapping distribution in brain with SRIF1 receptors [5].
• In contrast, SSTR5 bound very few SRIF analogues with high affinity [29].
• Membranes from a cell line exhibiting highest expression of SSTR2 gene bound SS and its analogue, octreotide, with moderate affinity [30].
• However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05) [25].
• These results indicate that human SSTR2 is functionally coupled to Gi alpha 1 protein but not to Gi alpha 2 or Gi alpha 3 when expressed in CHO cells [31].
• Given that SST analogs show preferential binding to SSTR2, these data provide a mechanism for their effectiveness in controlling pituitary tumors and the absence of tolerance seen in patients undergoing long-term administration [32].

Regulatory relationships of SSTR2

• SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms [25].
• Nevertheless, SRIF stimulated AC even in the presence of forskolin at higher doses of SRIF in PTX-treated hSSTR5-expressing cells [33].
• Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53 [34].
• However, somatostatin-14 inhibits the adenylyl cyclase in a dose dependent and pertussis toxin-sensitive manner when human SSTR2 is co-expressed with Gi alpha 1 in CHO cells [31].
• In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability [35].

Other interactions of SSTR2

• We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function [25].
• The subtype SSTR1 was expressed alone in 4 cases, SSTR2 was expressed alone in 33 cases, and SSTR3 was expressed alone in one case [3].
• Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors [36].
• Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005) [2].
• Moreover, SHP-1 associates with SSTR2 depending on its activation [37].

Analytical, diagnostic and therapeutic context of SSTR2

• To understand the molecular nature of selective peptide agonist binding to somatostatin receptors we have now, by site-directed mutagenesis, identified amino acids mediating SMS 201-995 specificity for SSTR2 [38].
• This is the first demonstration of the presence of SSTR1, SSTR2, and SSTR3 in primary human tumors using in situ hybridization [3].
• RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression [39].
• A PCR product of the expected size of 334 bp, corresponding to SSTR1, was expressed only in EC from prostate cancer, whereas the expected 461-bp product of SSTR2 was found only in EC from normal prostate [40].
• Nude mice bearing subcutaneous murine colon CA xenografts were injected intraperitoneally with the SSTR2-expressing VV or control VV [27].

References