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J. Biol. Chem., Vol. 282, Issue 19, 14283-14290, May 11, 2007

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Ca²⁺ Signaling in Microdomains

Homer1 MEDIATES THE INTERACTION BETWEEN RyR2 AND Cav1.2 TO REGULATE EXCITATION-CONTRACTION COUPLING^*

Guojin Huang, Joo Young Kim, Marlin Dehoff, Yusuke Mizuno, Kristine E. Kamm, Paul F. Worley^¶1, Shmuel Muallem^¶2, and Weizhong Zeng

From the Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 and Department of Neuroscience, Program in Biochemistry, Cellular, and Molecular Biology, ^¶Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Excitation-contraction (E-C) coupling and Ca²⁺-induced Ca²⁺ release in smooth and cardiac muscles is mediated by the L-type Ca²⁺ channel isoform Ca_v1.2 and the ryanodine receptor isoform RyR2. Although physical coupling between Ca_v1.1 and RyR1 in skeletal muscle is well established, it is generally assumed that Ca_v1.2 and RyR2 do not directly communicate either passively or dynamically during E-C coupling. In the present work, we re-examined this assumption by studying E-C coupling in the detrusor muscle of wild type and Homer1^-/- mice and by demonstrating a Homer1-mediated dynamic interaction between Ca_v1.2 and RyR2 using the split green fluorescent protein technique. Deletion of Homer1 in mice (but not of Homer2 or Homer3) resulted in impaired urinary bladder function, which was associated with higher sensitivity of the detrusor muscle to muscarinic stimulation and membrane depolarization. This was not due to an altered expression or function of RyR2 and Ca_v1.2. Most notably, expression of Ca_v1.2 and RyR2 tagged with the complementary C- and N-terminal halves of green fluorescent protein and in the presence and absence of Homer1 isoforms revealed that H1a and H1b/c reciprocally modulates a dynamic interaction between Ca_v1.2 and RyR2 to regulate the intensity of Ca²⁺-induced Ca²⁺ release and its dependence on membrane depolarization. These findings define the molecular basis of a "two-state" model of E-C coupling by Ca_v1.2 and RyR2. In one state, Ca_v1.2 couples to RyR2 by H1b/c, which results in reduced responsiveness to membrane depolarization and in the other state H1a uncouples Ca_v1.2 and RyR2 to enhance responsiveness to membrane depolarization. These findings reveal an unexpected and novel mode of interaction and communication between Ca_v1.2 and RyR2 with important implications for the regulation of smooth and possibly cardiac muscle E-C coupling.

Received for publication, December 18, 2006 , and in revised form, February 22, 2007.

^* This work was supported, in part, by a grant from the American Heart Association, Inc., Texas Affiliate BG1A 0665192Y (to W. Z.), National Institutes of Health Grants DE12309 and DK38938 and the Ruth S. Harrell Professorship in Medical Research (to S. M.), by the National Institute on Drug Abuse (DA00266, DA10309), and the National Institute of Mental Health (MH068830) (to P. F. 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.

¹ To whom correspondence may be addressed. E-mail: pworley{at}jhmi.edu. ² To whom correspondence may be addressed. E-mail: Shmuel.muallem{at}utsouthwestern.edu.

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