Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

Abstract

G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery.

Illuminating somatostatin analog action at neuroendocrine tumor receptors

“…Although the co-expression of sst subtypes may be overestimated by nonspecific antibody reactivity (see below) 21,22 , functional overlap of sst subtypes has been confirmed in a number of instances using somatostatin analogs. Moreover, experiments in cell lines expressing multiple transfected sst subtypes have demonstrated that some sst receptors are able to heterodimerize with other members of the sst receptor family as well as with unrelated GPCRs, including D2 dopamine receptors, β1 and β2 adrenergic receptors and ghrelin receptors 23,24 . Co-expression of such interacting receptors in a cell can affect sst receptor trafficking, signaling or biological activity.…”

Sunitinib in pancreatic neuroendocrine tumors. Clinical case

“…Радионуклидное исследование с рецептор-специфическим радиофармацевтическим препаратом (РФП) 111In-октреотидом обладает высокой диагностической эффективностью для НЭО с гиперэкспрессией рецепторов соматостатина на поверхности кле-ток. Это позволяет использовать методы радионуклидной диагностики для функциональной визуализации НЭО, оценки жизнеспособности опухолевых тканей и количественной оценки биологической активности [10] и рецепторного статуса опухоли, что предопределяет возможность и эффективность последующего применения аналогов соматостатина в случае наличия карциноидного синдрома либо опухолевой прогрессии.…”

“…SSTR 2 типа экспрессируются исключительно на мембране клеток, тогда как SSTR 1, 3 и 5 расположены внутриклеточно [9]. SSTR участвуют в регуляции индукции клеточного цикла, апоптоза, модуляции ангиогенеза и иммунной системы, высвобождении биологически активных веществ [10].…”

Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

“…Furthermore, the requirement of the N-methyl-D-aspartate receptor in the activation of AgRP neurons during fasting is important but uncertain physiologically in food-seeking process specifically in fasting [338]. Mounting evidence describes the protein-protein interaction between a member of GPCR family and SSTRs, DRs, opioid receptors, adrenergic receptor, and cannabinoid receptors, and their homo-and/or heterodimerization is well studied [339][340][341][342]. These prominent members of the GPCR family exert a crucial role, directly and/or indirectly, in the regulation of food-seeking behaviour [343].…”