Co-expression of the human cannabinoid receptor coding region splice variants (hCB1) affects the function of hCB1 receptor complexes

The human type 1 cannabinoid (hCB(1)) receptor is expressed at high levels in the central nervous system, mRNA variants of the coding region of this receptor, human cannabinoid hCB(1), and liC beta(1b), receptors, have been identified, their biological function remains unclear. The present study demonstrated that the three human cannabinoid hCB(1), coding region variants are expressed in the human and monkey (Macaca lascicularis) brain. Western blot analyses of homogenates from different regions of the monkey brain demonstrated that proteins with the expected molecular weights of the cannabinoid 031, CB1a,, and CB-a, receptors were co-expressed throughout the brain. Given the co-localization of these receptors, we hypothesized that physical interactions between the three splice variants may affect cannabinoid pharmacology. The human cannabinoid hCB1, hCB(1a), and hCB(1b) receptors formed homodimers and heterodimers, as determined by BRET in transiently transfected HEK 293A cells. We found that the coexpression of the human cannabinoid hCB1 and each of the splice variants increased cell surface expression of the human cannabinoid hCB1 receptor and increased Go-dependent ERK phosphorylation in response to cannabinoicl agonists. Therefore, the human cannabinoicl liCB(1) coding region splice variants play an important physiological role in the activity of the endocannabinoid system. (C) 2013 Elsevier B.V. All rights reservecl.