Physical and functional interaction between calcineurin and the cardiac L-type calcium channel

Show full item record

Title: Physical and functional interaction between calcineurin and the cardiac L-type calcium channel
Author: Tandan, Samvit
Abstract: The L -type Ca2+ channel is the major mediator of Ca2+ influx in cardiomyocytes leading to both mechanical contraction and activation of signaling cascades . Among these cascades is calcineurin , a protein phosphatase that promotes hypertrophic growth of the heart . We previously reported from in vivo models of pressure -overload that calcineurin regulates Ca2+ channel function in the heart , such that , inhibition of calcineurin activity results in a decrease in channel function . Based on this , we hypothesize that calcineurin participates in the channel macromolecular complex . Initial immunohistochemical data demonstrated evidence for co -localization of calcineurin to alpha1C , the pore -forming subunit of the L -type Ca2+ channel in mouse ventricular tissue . Additionally , co -immunoprecipitation biochemical experiments revealed evidence for binding between calcineurin and alpha1C in native mouse and rat heart tissues . Pulldown assays using GST -fusion proteins of all intracellular alpha1C regions provided evidence for direct binding of calcineurin at the N - and C -termini of alpha1C . At the C -terminus , calcineurin bound to aa 1909 -2029 overlapping the well -characterized PKA /PKC site Ser -1928 . In vitro kinase /phosphatase assays revealed Ser -1928 as a substrate for calcineurin dephosphorylation . Voltage -clamp recordings of L -type Ca2+ currents from cultured cardiomyocytes expressing constitutively -active calcineurin revealed significant up -regulation of channel function , similar to our previous observations from cardiac hypertrophy in vivo . Conversely , acute suppression of calcineurin , both pharmacologically or with specific peptide -inhibitors , induced a significant decrease in L -type channel function , while neither intervention had an effect on channel function in the absence of calcineurin activity . These data provide evidence for direct interaction between the L -type Ca2+ channel and calcineurin , and insights into the regulation of the channel by calcineurin . Furthermore , they highlight the specific role of calcineurin as a potential mediator of pathophysiological electrical remodeling in cardiac hypertrophy and failure .
URI: http : / /hdl .handle .net /2152 .5 /491
Date: 2008-09-19

Citation

Physical and functional interaction between calcineurin and the cardiac L-type calcium channel. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /491 .

Files in this item

Files Size Format View
tandansamvit.pdf 12.41Mb application/pdf View/Open

This item appears in the following Collection(s)

Show full item record

Search DSpace

Advanced Search

Browse