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Endocrinology Vol. 142, No. 3 1209-1217
Copyright © 2001 by The Endocrine Society

ARTICLES

Mechanisms of Phospholipase C Activation by the Vasoactive Intestinal Polypeptide/Pituitary Adenylate Cyclase-Activating Polypeptide Type 2 Receptor

Christopher J. MacKenzie1, Eve M. Lutz2, Melanie S. Johnson, Derek N. Robertson, Pamela J. Holland and Rory Mitchell

Medical Research Council Membrane and Adapter Proteins Co-operative Group, Membrane Biology Group, Department of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD; and Medical Research Council Brain Metabolism Unit, Edinburgh, United Kingdom EH8 9JZ

Address all correspondence and requests for reprints to: Dr. R. Mitchell, Medical Research Council Membrane and Adapter Proteins Co-operative Group, Membrane Biology Group, Department of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, United Kingdom EH8 9XD. E-mail: rory.mitchell{at}ed.ac.uk

The vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide type 2 (VPAC2) receptor was shown to induce both [3H]inositol phosphate ([3H]InsP)and cAMP production in transfected COS7 cells and in GH3 cells where it is natively expressed. Neither cholera toxin nor forskolin could elicit an equivalent [3H]InsP response, suggesting independent coupling of the two pathways. The VPAC2 receptor-mediated [3H]InsP response was partially inhibited by pertussis toxin (Ptx) and by the G{beta}{gamma}-sequestering C-terminal fragment of GRK2 (GRK2-ct) in COS7 and GH3 cells, whereas responses of control receptors were unaffected. Blockers of receptor-activated Ca2+ influx pathways (Co2+ and SKF 96365) also partially inhibited VPAC2 receptor-mediated [3H]InsP responses. This inhibition was not present in the component of the response remaining after Ptx treatment. A range of blockers of voltage-sensitive Ca2+ channels were ineffective, consistent with the reported lack of these channels in COS7 cells. The data suggest that the VPAC2 receptor may couple to phospholipase C through both Ptx-insensitive and Ptx-sensitive G proteins (Gq/11 and Gi/o, respectively) to generate [3H]InsP. In addition to G{beta}{gamma}, Gi/o activation appears to require receptor-activated Ca2+ entry. This is consistent with the possibility that not only G{alpha}q/11-responsive and G{beta}{gamma}-responsive isoforms of phospholipase C but also Ca2+-responsive forms may contribute to the overall [3H]InsP response.




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