title: Phorbol 12,13-dibutyrate regulates muscarinic receptors in rat cerebral cortical slices by activating protein kinase C.
abstract: Stimulation of muscarinic acetylcholine receptors (mAChR) elicits phosphatidylinositol turnover, which yields inositol phosphates (InsP) and diacylglycerol (DG) the latter activating protein kinase C (PKC). Activating PKC with phorbol esters inhibits mAChR agonist-stimulated phosphoinositide hydrolysis and InsP production. A possible mechanism of this inhibition may be down-regulation of mAChR by PKC. In the present work, rat cortical slices were preincubated with phorbol 12,13-dibutyrate (PDBu) followed by binding assays for [3H]quinuclidinyl benzilate [( 3H]QNB), [N-methyl-3H]scopolamine [( 3H]NMS) or [3H]pirenzepine [( 3H]PZ). Our data demonstrate that activation of PKC by phorbol esters causes a rapid down-regulation of muscarinic cholinergic receptors. This down-regulation is also rapidly reversible. Receptors on the cell surface appear to be more sensitive to the effect of PKC than do internal ones. This down-regulation occurs by a decrease in the number of receptors, rather than by changes in receptor affinity. The results suggest that PKC may exert negative feedback on its own activation by down-regulating the receptors that normally elicit phosphatidylinositol turnover.
authors.affiliation: Department of Ophthalmology, University of British Columbia, Vancouver, Canada.
authors.forename: W G
authors.initials: WG
authors.lastname: Jia
authors.forename: C
authors.initials: C
authors.lastname: Shaw
authors.forename: F
authors.initials: F
authors.lastname: van Huizen
authors.forename: M S
authors.initials: MS
authors.lastname: Cynader
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010890:Pirenzepine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012601:Scopolamine / Q000378:metabolism
chemical_list: D011976:Receptors, Muscarinic; D015240:Phorbol 12,13-Dibutyrate; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate; D012601:Scopolamine; D011494:Protein Kinases