Ca2+ entry through plasma membrane L-type (Cav1.2) Ca2+ channels regulates many essential biological functions including muscle contraction, hormone release, and gene expression. Dysregulation of L-type channel functional expression underlies a wide range of diseases including life-threatening atrial arrhythmias, autism, night blindness, and deafness. Moreover, L-type channels are important therapeutic targets for a number of diseases that constitute a significant detriment to the public health such as hypertension, angina, and arrhythmias. Nevertheless, there are significant gaps in knowledge regarding the precise role of L-type channels in the pathogenesis of various diseases, and their full therapeutic potential remains largely unrealized. A key contributor to the impasse is lack of fundamental mechanistic insights into processes underlying L-type channel sub-cellular targeting and gating behavior. Our long-term objective is two fold: first, to increase fundamental molecular understanding of structure-function mechanisms underlying L-type channel functional expression; second, to bridge these basic insights to a new realization of the (patho)physiological roles and therapeutic potential of L-type channels. We combine electrophysiological assays of recombinant and native L-type (Cav1.2) channels, FRET detection of protein interactions, and immounofluorescence detection of channel subunits in 4 Aims: 1. Clarify the role of auxiliary Cav? structural determinants underlying trafficking and gating-modulation of recombinant L-type channel a1C subunits. 2. Clarify a1C structural determinants important for interacting with Cav?s, and define their role in channel trafficking and gating-modulation. 3. Define the structural determinants underlying targeting of L-type Ca2+channels to dyadic junctions in heart. 4. Elucidate molecular determinants and mechanisms of protein kinase A modulation of cardiac L-type Ca2+channels. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL069911-06
Application #
7528933
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2002-04-15
Project End
2012-06-30
Budget Start
2007-12-21
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$388,580
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Liu, Nan; Yang, Yaxiong; Ge, Lin et al. (2017) Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels. Elife 6:
Yang, Tingting; Hendrickson, Wayne A; Colecraft, Henry M (2014) Preassociated apocalmodulin mediates Ca2+-dependent sensitization of activation and inactivation of TMEM16A/16B Ca2+-gated Cl- channels. Proc Natl Acad Sci U S A 111:18213-8
Shaw, Robin M; Colecraft, Henry M (2013) L-type calcium channel targeting and local signalling in cardiac myocytes. Cardiovasc Res 98:177-86
Subramanyam, Prakash; Chang, Donald D; Fang, Kun et al. (2013) Manipulating L-type calcium channels in cardiomyocytes using split-intein protein transsplicing. Proc Natl Acad Sci U S A 110:15461-6
Yang, Tingting; He, Lin-Ling; Chen, Ming et al. (2013) Bio-inspired voltage-dependent calcium channel blockers. Nat Commun 4:2540
Yang, Tingting; Colecraft, Henry M (2013) Regulation of voltage-dependent calcium channels by RGK proteins. Biochim Biophys Acta 1828:1644-54
Yang, Tingting; Puckerin, Akil; Colecraft, Henry M (2012) Distinct RGK GTPases differentially use ýý1- and auxiliary ýý-binding-dependent mechanisms to inhibit CaV1.2/CaV2.2 channels. PLoS One 7:e37079
Fang, Kun; Colecraft, Henry M (2011) Mechanism of auxiliary ýý-subunit-mediated membrane targeting of L-type (Ca(V)1.2) channels. J Physiol 589:4437-55
Xu, Xianghua; Marx, Steven O; Colecraft, Henry M (2010) Molecular mechanisms, and selective pharmacological rescue, of Rem-inhibited CaV1.2 channels in heart. Circ Res 107:620-30
Yang, Tingting; Xu, Xianghua; Kernan, Timothy et al. (2010) Rem, a member of the RGK GTPases, inhibits recombinant CaV1.2 channels using multiple mechanisms that require distinct conformations of the GTPase. J Physiol 588:1665-81

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