Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C

Biochemistry
G W DornS B Liggett

Abstract

Proposed mechanisms by which alpha 2-adrenergic receptors (alpha 2AR) regulate intracellular calcium ([Ca2+]i) include stimulation and inhibition of cell surface calcium channels, stimulation of calcium release via receptor coupling to Gq with subsequent activation of phospholipase C and release of IP3, or stimulation of calcium release via coupling to Gi in an IP3-independent manner. These potential mechanisms were explored in cells that expressed alpha(2A)AR endogenously (HEL cells), permanently transfected CHO cells, and transiently transfected COS-7 cells. Each cell type displayed agonist (UK14304)-dependent increases in [Ca2+]i that were blocked by yohimbine, ablated by pertussis toxin, and largely unaffected by chelation of extracellular calcium. Furthermore, calcium release was associated with IP3 accumulation and was blocked by an inhibitor of phospholipase C (PLC). When expressed in CHO cells, a mutated alpha(2A)AR which has the amino and carboxyl termini of the third intracellular loop substituted with beta 2AR sequence poorly coupled to Gi in adenylyl cyclase assays, and likewise displayed virtually no coupling to increased [Ca2+]i. These results all point toward a Gi- versus a Gq-mediated coupling pathway triggering...Continue Reading

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