G Protein Coupling of Receptor Activation to Lacrimal Secretion

Abstract

In lacrimal gland, protein secretion involves transduction of extracellular signals generated by neurotransmitters and neuromodulators of the parasympathetic and sympathetic nerve fibers that innervate the gland. In this gland, as in other exocrine tissues, transmembrane signalling is accomplished by the adenosine 3’,5’-cyclic monophosphate (cAMP) and the inositol 1,4,5-trisphosphate (IP₃) pathways. In the cAMP pathway, vasoactive intestinal peptide (VIP) stimulates and met-enkephalin inhibits the regulatory effector enzyme adenylyl cyclase and the consequent alterations in intracellular cAMP that result in stimulation or inhibition of protein release by lacrimal acinar cells.^1,2 Agonists that activate phosphatidylinositol turnover also stimulate release of protein into the tears.^3,4 In this pathway, M₃-muscarinic receptor activation results in an increase in phosphatidylinositol 4,5-bisphosphate (PIP₂)-specific phospholipase C (PLC) activity and the production of IP₃.⁵ Within both intracellular pathways, heterotrimeric G proteins couple receptor activation to regulation of the effector enzymes adenylyl cyclase and PLC. We have demonstrated that the stimulatory G protein G_S and inhibitory G proteins of the G_i/G_o family are present in lacrimal gland membranes and that the a subunits of these G proteins are specifically associated with VIP and enkephalin regulation of adenylyl cyclase.^6,7 We have also demonstrated that G_q/11, known to be coupled to PLC,⁸ is present in lacrimal acinar cell membranes.⁹ Thus, our previous work has established G protein coupling of receptors to adenylyl cyclase and provided preliminary evidence for coupling of G_q/11 to PLC in lacrimal gland.