Disease relevance of Sstr2

• To test the involvement of SMST receptor 2 (SMSTR2) in pituitary tumor progression and thyroid hormone responsiveness in alphaGsu(-/-) mutants, we generated Smstr2(-/-), alphaGsu(-/-) mice [1].
• Thyrotrope hyperplasia in Smstr2(-/-), alphaGsu(-/-) mice regresses in response to T4 treatment, suggesting that SMSTR2 is not required in the T4 feedback loop regulating TSH secretion [1].
• These data show that pertussis toxin-insensitive activation of the sst1 receptor subtype mediates somatostatin-induced increase in sensitivity to glutamate, whereas decrease in the response to glutamate is linked to pertussis toxin-sensitive activation of the sst2 receptor subtype [2].
• Somatostatin (SRIF) controls many physiological and pathological processes in the central nervous system but the respective roles of the five receptor isotypes (sst1-5) that mediate its effects are yet to be defined [3].
• Monoclonal antibodies [SRIF, protein kinase C (rod bipolar cells marker), microtubule associated protein 1A (ganglion cell marker)] and polyclonal antibodies (anti-sst(1), sst(2A), sst(4) receptor) were applied to 10-14mum sections of retinas fixed in paraformaldehyde [4].

Psychiatry related information on Sstr2

• In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks [5].
• Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered [6].

High impact information on Sstr2

• Moreover anti-somatostatin antibodies suppressed sst2-promoted inhibition of cell proliferation [7].
• In the absence of exogenous ligand, expression of sst2 in NIH 3T3 cells resulted in inhibition of cell growth [7].
• The somatostatin receptor subtype sst2 mediates both activation of a tyrosine phosphatase activity and inhibition of cell proliferation induced by somatostatin analogues [7].
• The role of sst2 in the regulation of acid secretion was assessed using sst2 knockout mice and urethane to induce somatostatin release [8].
• BACKGROUND & AIMS: Somatostatin receptor subtype 2 (sst2) agonists inhibit gastric secretion [8].

Chemical compound and disease context of Sstr2

• Thyroid hormone-responsive pituitary hyperplasia independent of somatostatin receptor 2 [1].
• Results from sst1 KO retinas demonstrate that either SRIF or the sst2 receptor preferring agonist octreotide, pertussis toxin-dependently inhibit AC activity [9].
• The potential effects of pertussis toxin pretreatment on the inhibitory effect of somatostatin (SRIF) and the selective SRIF receptor agonist, seglitide, were studied in mouse vas deferens and these were compared with its effect on the negative chronotropic action of carbachol in mouse atria [10].
• Both adenovirus- and PEI-mediated in vivo gene transfer in primary pancreatic tumors induced an increase of beta-galactosidase activity and expression of sst2 transgene nRNA (100% and 86% of tumors for adenovirus and PEI vector, respectively) [11].
• Somatostatin (SRIF) receptors are coupled to the catalytic subunit of adenylyl cyclase via pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins (G proteins) [12].

Biological context of Sstr2

• In an investigation of the molecular mechanisms controlling these patterns, we have recently shown that binding of the transcription factor SEF-2 to a novel initiator element in the SSTR-2 promoter is essential for SSTR-2 gene expression [13].
• SSTR2A and SSTR2B are generated by alternative splicing of SSTR2 mRNA [14].
• These findings differ from the results of similar mutagenesis studies on other G protein-linked receptors, in that the mutant and wild-type SSTR2 forms associate with G proteins in similar ways [15].
• SRIF-1 binding site radioautography indicated that 10% of hypothalamic neurons were labelled on both cell bodies and neuritic processes, as were 35% of astrocytes [16].
• We conclude that sst2 compensates for SRIF absence and that its upregulation is responsible for reduced bursting and decreased excitatory transmission in KO mice [17].

Anatomical context of Sstr2

• Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra [5].
• In the body of the stomach, a large proportion of epithelial cells and subpopulations of myenteric neurons expressed Sstr2 [18].
• In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons [5].
• Most of Sstr2-expressing neurons in the myenteric plexus showed nitric oxide synthase (NOS) immunoreactivity [18].
• Identification of cells expressing somatostatin receptor 2 in the gastrointestinal tract of Sstr2 knockout/lacZ knockin mice [18].

Associations of Sstr2 with chemical compounds

• Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release [5].
• METHODS: Acid secretion was monitored every 10 minutes by gastric perfusion and backtitration of perfusates in fasted, urethane-anesthetized C57/129 sst2 (-/-) mice and wild-type (+/+) mice [8].
• Somatostatin 14 or the sst2 agonist DC 32-87 inhibited pentagastrin-stimulated acid secretion in wild-type mice, but did not alter basal secretion in knockout mice [8].
• The two receptors exhibited similar affinities for a number of SSTR2-selective agonists such as MK-678 [14].
• On neuronal and glial membranes, SRIF-14 and octreotide, an sst2/sst3/sst5-selective analogue, completely displaced SRIF-1 binding, whereas des-AA(1,2,5)[D-Trp8,IAmp9]SRIF (CH-275), an sst1-selective analogue, was ineffective [16].

Physical interactions of Sstr2

• Several regions of the brain reported to contain dense somatostatin-like immunoreactive terminal fields and receptor binding sites were devoid of both SSTR1 and SSTR2 mRNA, suggesting the existence of additional SSTR subtypes [19].

Regulatory relationships of Sstr2

• GHRH ARC neurons expressing sst2, but not sst1, receptors were always connected with PEV neurons [20].
• The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice [21].
• The inhibitory effect of both somatostatin and L-779976 on secretin-induced IBDU secretion was absent in IBDUs of SSTR2 knockout mice [22].
• Desensitization and down-regulation of sst 2 after agonist exposure can have important consequences for patients under ongoing octreotide therapy because it may induce temporary tumor unresponsiveness and impair sst 2-based tumor scintigraphy [23].
• L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2 [24].

Other interactions of Sstr2

• Somatostatin receptor type 5 modulates somatostatin receptor type 2 regulation of adrenocorticotropin secretion [25].
• Na+ reduced agonist binding to SSTR2 but not to SSTR1 [15].
• In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst2, suggesting that sst2 and sst4 are functionally coupled in the WT hippocampus [17].
• The gastrin antibody abolished the high basal acid secretion in sst2 (-/-) mice and had no effect in wild-type mice [8].
• In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5 [21].

Analytical, diagnostic and therapeutic context of Sstr2

• By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2 [5].
• Somatostatin receptor subtypes sst1 and sst2 elicit opposite effects on the response to glutamate of mouse hypothalamic neurones: an electrophysiological and single cell RT-PCR study [2].
• Amplification of mRNA by reverse transcription PCR shows SSTR1, SSTR2, and SSTR3 mRNA in normal mouse brain and other tissues [26].
• In Chinese hamster ovary (CHO) cells stably expressing the mouse SSTR2 gene (CHOB), the antibody 2e3 recognized specifically a protein of 93-kDa protein by immunoblotting [27].
• This suggests that SSTR1 is involved in modulating basal GH levels in primary pituitary cell cultures and, together with SSTR2, may control the secretion of GH in the body [28].

References