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

We used co-immunoprecipitation, photobleaching- fluorescence resonance energy transfer and Fluorescence assisted cell sorting analysis to characterize heterodimerization between SSTR5 and β2AR.Our 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.These 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.We have recently described homo-and heterodimerization of somatostatin receptor (SSTR) subtypes and its functional consequences on receptor trafficking and signaling in response to agonist activation. SSTRs heterodimerization is not restricted to its own family but has also been demonstrated with other member of G-protein coupled receptors (GPCRs) family such as dopamine and opioid receptors as well as with the members of receptor tyrosine kinase family [1-4]. In several pathological conditions including neurodegenerative diseases and tumors of different origin, somatostatin (SST) via its five receptor subtypes plays crucial role and serves as an important therapeutic approach. Most recent example of clinical implication of heterodimerization is the development of chimeric molecules of hSSTR5 and dopamine receptor 2 in treatment of pituitary tumor [5,6].Adrenergic receptors (ARs) specifically β1AR and β2AR are the prominent receptor subtypes from GPCR family and ha