Abstract
Somatostatin receptors (SSTRs) are G protein-coupled receptors (GPCRs) known to regulate exocrine secretion, neurotransmission, and inhibit endogenous cell proliferation. SSTR subtypes (SSTR1-SSTR5) exhibit homo- or heterodimerization with unique signaling characteristics. Melanocortin receptor accessory protein 1 (MRAP1) functions as an allosteric modulator of melanocortin receptors and some other GPCRs. In this study, we investigated the differential interaction of MRAP1 and SSTRs and examined the pharmacological modulation of MRAP1 on mouse SSTR2/SSTR3 and SSTR2/SSTR5 heterodimerization in vitro. Our results show that the mouse SSTR2 forms heterodimers with SSTR3 and SSTR5 and that MRAP1 selectively interacts with SSTR3 and SSTR5 but not SSTR2. The interactive binding sites of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 locate on SSTR3 and SSTR5 but not SSTR2. The binding sites of MRAP1 to SSTR3 are extensive, while the ones of SSTR5 are restricted on transmembrane region six and seven. The heterodimerization of mouse SSTR2, SSTR3, and SSTR5 can be modulated by binding protein in addition to an agonist. Upregulation of extracellular signal-regulated kinases phosphorylation, p27Kip1, and increased cell growth inhibition with the co-expression of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 suggest a regulatory effect of MRAP1 on anti-proliferative response of two SSTR heterodimers. Taken together, these results provide a new insight of MRAP1 on the maintenance and regulation of mouse SSTR dimers which might be helpful to better understand the molecular mechanism involving SSTRs in tumor biology or other human disorders.
Highlights
As a hypothalamic neuroendocrine hormone, somatostatin exerts its biological functions via five receptor subtypes, somatostatin receptor (SSTR) 1–5
The neighbor joining phylogenetic tree was analyzed based on the amino acid sequences and results showed that in the somatotropin release inhibiting factor receptor 2 (SRIF2) subgroup, SSTR1 was more similar to SSTR4, while SSTR2, SSTR3 and SSTR5 were classified into the somatotropin release inhibiting factor receptor 1 (SRIF1) subgroup (Figure 1B)
It is considered to have a functional association between SSTR2/SSTR5 heterodimers and rarely tachyphylaxis of patients on somatostatin analogs despite years of continuous administration [20]
Summary
As a hypothalamic neuroendocrine hormone, somatostatin exerts its biological functions via five receptor subtypes, somatostatin receptor (SSTR) 1–5. All SSTR subtypes belong to the family of seven transmembrane domain of G protein-coupled receptors (GPCRs) couple to guanine nucleotide-binding protein G(i) subunit alpha [5,6]. GPCRs play a key role in transmitting various extracellular signals into cells and regulating diverse physiological functions. Cyclic adenosine monophosphate (cAMP) inhibition was enhanced upon SSTRs activation [7]. Based on SSTR sequence homology and their pharmacological properties, the receptor subtypes can be classified to two subclasses: somatotropin release inhibiting factor receptor 1 (SRIF1) and somatotropin release inhibiting factor receptor 2 (SRIF2)
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