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J. Biol. Chem., Vol. 279, Issue 20, 21461-21468, May 14, 2004

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Ca²⁺-sensing Transgenic Mice

POSTSYNAPTIC SIGNALING IN SMOOTH MUSCLE^*

Guangju Ji, Morris E. Feldman, Ke-Yu Deng, Kai Su Greene, Jason Wilson, Jane C. Lee, Robyn C. Johnston, Mark Rishniw, Yvonne Tallini, Jin Zhang, Winthrop G. Wier, Mordecai P. Blaustein, Hong-Bo Xin, Junichi Nakai¶, and Michael I. Kotlikoff||

From the Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, the Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, and the ^¶Laboratory for Neuronal Circuit Dynamics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Genetically encoded signaling proteins provide remarkable opportunities to design and target the expression of molecules that can be used to report critical cellular events in vivo, thereby markedly extending the scope and physiological relevance of studies of cell function. Here we report the development of a transgenic mouse expressing such a reporter and its use to examine postsynaptic signaling in smooth muscle. The circularly permutated, Ca²⁺-sensing molecule G-CaMP (Nakai, J., Ohkura, M., and Imoto, K. (2001) Nat. Biotechnol. 19, 137-141) was expressed in vascular and non-vascular smooth muscle and functioned as a lineage-specific intracellular Ca²⁺ reporter. Detrusor tissue from these mice was used to identify two separate types of postsynaptic Ca²⁺ signals, mediated by distinct neurotransmitters. Intrinsic nerve stimulation evoked rapid, whole-cell Ca²⁺ transients, or "Ca²⁺ flashes," and slowly propagating Ca²⁺ waves. We show that Ca²⁺ flashes occur through P2X receptor stimulation and ryanodine receptor-mediated Ca²⁺ release, whereas Ca²⁺ waves arise from muscarinic receptor stimulation and inositol trisphosphate-mediated Ca²⁺ release. The distinct ionotropic and metabotropic postsynaptic Ca²⁺ signals are related at the level of Ca²⁺ release. Importantly, individual myocytes are capable of both postsynaptic responses, and a transition between Ca²⁺-induced Ca²⁺ release and inositol trisphosphate waves occurs at higher synaptic inputs. Ca²⁺ signaling mice should provide significant advantages in the study of processive biological signaling.

Received for publication, January 30, 2004

^* This work was supported by National Institutes of Health Grants HL045239, D58795, and DK065992 (to M. I. K.), HL45215 (to M. P. B.), and HL64708 (to W. G. W.). 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.

^|| To whom correspondence should be addressed: Dept. of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T4018 VRT, Box 11, Ithaca, NY 14853-6401. Tel.: 607-253-3336; Fax: 607-253-4447; E-mail: mik7{at}cornell.edu.

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