A rapid attenuation of muscarinic agonist stimulated phosphoinositide hydrolysis precedes receptor sequestration in human SH-SY-5Y neuroblastoma cells |
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Authors: | Dr. Stephen K. Fisher Diana M. Slowiejko Edward L. McEwen |
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Affiliation: | (1) Department of Pharmacology, University of Michigan, 48104-1687 Ann Arbor, MI;(2) Neuroscience Laboratory, University of Michigan, 1103 E. Huron St., 48104-1687 Ann Arbor, MI |
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Abstract: | Agonist occupancy of muscarinic cholinergic receptors in human SH-SY-5Y neuroblastoma cells elicited two kinetically distinct phases of phosphoinositide hydrolysis when monitored by either an increased mass of inositol 1,4,5-trisphosphate, or the accumulation of a total inositol phosphate fraction. Within 5s of the addition of the muscarinic agonist, oxotremorine-M, the phosphoinositide pool was hydrolyzed at a maximal rate of 9.5%/min. This initial phase of phosphoinositide hydrolysis was short-lived (t1/2=14s) and after 60s of agonist exposure, the rate of inositol lipid breakdown had declined to a steady state level of 3.4%/min which was then maintained for at least 5–10 min. This rapid, but partial, attenuation of muscarinic receptor stimulated phosphoinositide hydrolysis occurred prior to the agonist-induced internalization of muscarinic receptors.Abbreviations I(1,4,5)P3 inositol 1,4,5-trisphosphate - IP total inositol phosphate fraction - IPL total inositol lipid fraction - mAChR muscarinic acetylcholine receptor - NMS N-methylscopolamine - Oxo-M oxotremorine-M - PI phosphatidylinositol - PIP phosphatidylinositol 4-phosphate - PIP2 phosphatidylinositol 4,5-bisphosphate - PPI phosphoinositide - QNB quinuclidinyl benzilateSpecial issue dedicated to Dr. Bernard W. Agranoff |
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Keywords: | Muscarinic cholinergic receptor phosphoinositide hydrolysis inositol 1,4,5-trisphosphate SH-SY-5Y neuroblastoma desensitization |
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