Heterodimerization of β₂ adrenergic receptor and somatostatin receptor 5: Implications in modulation of signaling pathway

Abstract

BackgroundIn the present study, we describe heterodimerization between human-Somatostatin Receptor 5 (hSSTR5) and β2-Adrenergic Receptor (β2AR) and its impact on the receptor trafficking, coupling to adenylyl cyclase and signaling including mitogen activated protein kinases and calcineurin-NFAT pathways.MethodsWe used co-immunoprecipitation, photobleaching- fluorescence resonance energy transfer and Fluorescence assisted cell sorting analysis to characterize heterodimerization between SSTR5 and β2AR.ResultsOur results indicate that hSSTR5/β2AR exist as preformed heterodimers in the basal condition which is enhanced upon co-activation of both receptors. In contrast, the activation of individual receptors leads to the dissociation of heterodimers. Receptor coupling to adenylyl cyclase displayed predominant effect of β2AR, however, somatostatin mediated inhibition of cAMP was enhanced upon blocking β2AR. Our results indicate hSSTR5 mediated significant activation of ERK1/2 and inhibition of phospho-p38. The phospho-NFAT level was enhanced in cotransfected cells indicating the blockade of calcineurin mediated dephosphorylation of NFAT upon receptor heterodimerization.ConclusionThese data for the first time unveil a novel insight for the role of hSSTR5/β2AR in the modulation of signaling pathways which has not been addressed earlier.

Cross-talk and modulation of signaling between somatostatin and growth factor receptors

“…SSTR subtypes not only heterodimerize within the family but does so with other members of GPCR family like dopamine, opioid, adrenergic, and growth factor receptors [28,30,31,[34][35][36][37][38][39][40][41][42][43]. In addition to displaying receptorspecific dimerization, SSTR subtypes have shown great diversity upon heterodimerization as well.…”

“…With respect to the formation of SSTR2 and D2R heterodimers, dopamine affinity was increased and SSTR2 functions remained unchanged [35]. Furthermore, recent studies have also described that SSTR1 and SSTR5 functionally interact with adrenergic and growth factor receptors with significant changes in receptor coupling to adenylyl cyclase and signaling in receptor specific manner [39][40][41][42][43]. Whether, the activation of two receptors in the presence of receptor-specific agonist also elicit similar effects in cells expressing these receptor endogenously is largely elusive.…”

The Intraviral Protein Interaction Network of Hepatitis C Virus

“…We established and used this technique in the past to demonstrate and map, for instance, the interaction of HIV-1 Vpu and Ebola GP2 with the antiviral factor Tetherin/Bst-2 (6,18,19) and to show the interplay between HIV-1 Gag and tetraspanins (34). Also, other groups used our FACS-FRET approach to show direct protein interactions, confirming independently the robustness of the assay (35)(36)(37)(38). Of note, Kim and coworkers systematically compared FACS-FRET, bioluminescence resonance energy transfer, and fluorescence lifetime imaging microscopy (22).…”

G-Protein Coupled Receptors Dimerization: Diversity in Somatostatin Receptors Subtypes

“…Although, studies have described the pharmacological and physiological significance of SSTRs, however the role of SSTR subtypes in pathological conditions still remains elusive. SSTR subtypes not only interact as heterodimers with other closely related receptors including DR, AR and OR subtypes but also constitute functionally active complex with distantly related receptor protein such as NMDA receptors of ionotropic and epidermal growth factor receptors (EGFRs) of receptor tyrosine kinase (RTKs) families and govern many clinical implications [54,55,63,[124][125][126]. If not all, most of the GPCR functions as homo-or heterodimers and the process of heterodimerization may enhance the existing functions of the native receptor.…”

“…The possibility of functional crosstalk between SSTRs and ORs or/and adrenergic receptors may provide some pathophysiological significance in pain and heart failure respectively [124][125][126]. Recent studies from author laboratory describing that SSTRs functionally interact with EGFR and modulate tumors promoting signaling pathways are of great importance to understand the pathological significance of inverse relation of these two receptor proteins in tumor biology [54][55][56].…”