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NEUROPHARMACOLOGY

Potentiation of the Osmosensitive Release of Taurine and D-Aspartate from SH-SY5Y Neuroblastoma Cells after Activation of M₃ Muscarinic Cholinergic Receptors

Mental Health Research Institute (A.M.H., D.K., G.T.G., A.T.V., S.K.F.) and Department of Pharmacology (S.K.F.), University of Michigan, Ann Arbor, Michigan

The ability of muscarinic cholinergic receptors (mAChRs) to regulate the volume-sensitive efflux of two organic osmolytes, namely, taurine and D-aspartate, from human SH-SY5Y neuroblastoma cells has been examined. Incubation of the cells with hypoosmolar buffers resulted in an efflux of both osmolytes, with the threshold for release occurring at approximately 225 mOsM for taurine and D-aspartate. Inclusion of oxotremorine-M (Oxo-M), a muscarinic agonist, resulted in a marked enhancement of the volume-dependent efflux of both osmolytes and increased the threshold osmolarity for taurine and D-aspartate release to 340 (isotonic) and 320 mOsM, respectively. Maximum agonist stimulation of osmolyte release (350% of basal) was observed in the range of 225 to 250 mOsM. Oxo-M-stimulated osmolyte efflux was inhibited by muscarinic antagonists with a rank order of potency 4-diphenylacetoxy-N-methylpiperidine methiodide > pirenzepine > 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, a pharmacological profile identical to that obtained for M₃ mAChR-stimulated phosphoinositide hydrolysis. Agonist-stimulated efflux of both osmolytes could be inhibited by inclusion of either anion channel blockers known to inhibit the volume-sensitive organic anion channel (VSOAC) or by a tyrosine kinase inhibitor -cyano-(3,4-dihydroxy)cinnamonitrile. The results indicate that the activation of M₃ mAChRs on SH-SY5Y neuroblastoma facilitates the ability of these cells to respond to very limited reductions in osmolarity via a release of osmolytes. mAChR-stimulated osmolyte efflux is mediated via a VSOAC and seems to require the activity of a tyrosine kinase.

Address correspondence to: Dr. Stephen K. Fisher, Mental Health Research Institute Laboratories at MSRB II, 1150 West Medical Center Dr., C560, MSRB II, University of Michigan, Ann Arbor, MI 48109-0669. E-mail: skfisher{at}umich.edu

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