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J. Biol. Chem., Vol. 279, Issue 47, 49036-49044, November 19, 2004

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Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca²+ Release in Hippocampal Neurons^*

Mark S. Nash, Jonathon M. Willets, Brian Billups, R. A. John Challiss, and Stefan R. Nahorski

From the Department of Cell Physiology & Pharmacology, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester, LE1 9HN, United Kingdom

Intracellular Ca²⁺ store release contributes to activity-dependent synaptic plasticity in the central nervous system by modulating the amplitude, propagation, and temporal dynamics of cytoplasmic Ca²⁺ changes. However, neuronal Ca²⁺ stores can be relatively insensitive to increases in the store-mobilizing messenger inositol 1,4,5-trisphosphate (IP₃). Using a fluorescent biosensor we have visualized M₁ muscarinic acetylcholine (mACh) receptor signaling in individual hippocampal neurons and observed increased IP₃ production in the absence of concurrent Ca²⁺ store release. However, coincident glutamate-mediated synaptic activity elicited enhanced and oscillatory IP₃ production that was dependent upon ongoing mACh receptor stimulation and S--amino-3-hydroxy-5-methyl-4-isoazolepropionic acid receptor activation of Ca²⁺ entry. Moreover, the enhanced levels of IP₃ now mobilized Ca²⁺ from intracellular stores that were refractory to the activation of mACh receptors alone. We conclude that convergent ionotropic and metabotropic receptor inputs can facilitate Ca²+ signaling by enhancing IP₃ production as well as augmenting release by Ca²⁺-induced Ca²⁺ release.

Received for publication, June 29, 2004 , and in revised form, August 27, 2004.

^* This work was supported by Program Grant 062495 from the Wellcome Trust of Great Britain. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Novartis Institute of Medical Sciences, 5 Gower Pl., London, WC1E 6BS, UK.

To whom correspondence should be addressed: Dept. of Cell Physiology & Pharmacology, University of Leicester, Maurice Shock Medical Sciences Bldg., University Rd., Leicester, LE1 9HN, UK. Tel.: 44-116-252-2920; E-mail: jc36{at}le.ac.uk.

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