TY - JOUR
T1 - CaBP1 regulates voltage-dependent inactivation and activation of Ca V1.2 (L-type) calcium channels
AU - Oz, Shimrit
AU - Tsemakhovich, Vladimir
AU - Christel, Carl J.
AU - Lee, Amy
AU - Dascal, Nathan
PY - 2011/4/22
Y1 - 2011/4/22
N2 - CaBP1 is a Ca2+-binding protein that regulates the gating of voltage-gated (CaV) Ca2+ channels. In the Ca V1.2 channel α1-subunit (α1C), CaBP1 interacts with cytosolic N-and C-terminal domains and blunts Ca 2+-dependent inactivation. To clarify the role of the α1C N-terminal domain in CaBP1 regulation, we compared the effects of CaBP1 on two alternatively spliced variants of α1C containing a long or short N-terminal domain. In both isoforms, CaBP1 inhibited Ca2+-dependent inactivation but also caused a depolarizing shift in voltage-dependent activation and enhanced voltage-dependent inactivation (VDI). In binding assays, CaBP1 interacted with the distal third of the N-terminal domain in a Ca2+-independent manner. This segment is distinct from the previously identified calmodulin-binding site in the N terminus. However, deletion of a segment in the proximal N-terminal domain of both α1C isoforms, which spared the CaBP1-binding site, inhibited the effect of CaBP1 on VDI. This result suggests a modular organization of the α1C N-terminal domain, with separate determinants for CaBP1 binding and transduction of the effect on VDI. Our findings expand the diversity and mechanisms of CaV channel regulation by CaBP1 and define a novel modulatory function for the initial segment of the N terminus of α1C.
AB - CaBP1 is a Ca2+-binding protein that regulates the gating of voltage-gated (CaV) Ca2+ channels. In the Ca V1.2 channel α1-subunit (α1C), CaBP1 interacts with cytosolic N-and C-terminal domains and blunts Ca 2+-dependent inactivation. To clarify the role of the α1C N-terminal domain in CaBP1 regulation, we compared the effects of CaBP1 on two alternatively spliced variants of α1C containing a long or short N-terminal domain. In both isoforms, CaBP1 inhibited Ca2+-dependent inactivation but also caused a depolarizing shift in voltage-dependent activation and enhanced voltage-dependent inactivation (VDI). In binding assays, CaBP1 interacted with the distal third of the N-terminal domain in a Ca2+-independent manner. This segment is distinct from the previously identified calmodulin-binding site in the N terminus. However, deletion of a segment in the proximal N-terminal domain of both α1C isoforms, which spared the CaBP1-binding site, inhibited the effect of CaBP1 on VDI. This result suggests a modular organization of the α1C N-terminal domain, with separate determinants for CaBP1 binding and transduction of the effect on VDI. Our findings expand the diversity and mechanisms of CaV channel regulation by CaBP1 and define a novel modulatory function for the initial segment of the N terminus of α1C.
UR - http://www.scopus.com/inward/record.url?scp=79954606201&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.198424
DO - 10.1074/jbc.M110.198424
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C2 - 21383011
AN - SCOPUS:79954606201
SN - 0021-9258
VL - 286
SP - 13945
EP - 13953
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -