Inactivation of L-type calcium channel modulated by HCN2 channel.
Ca(2+) entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit alpha1C and the auxiliary subunits beta1 and alpha2delta. Calmodulin is the key protein that interacts with the COOH-terminal motifs of alpha1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide-gated channel, HCN2, can act as a nonchannel regulatory protein to narrow the L-type Ca(2+) channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce alpha1C inactivation. Without alpha2delta, HCN2-induced fast inactivation of alpha1C requires calmodulin. With alpha2delta, the alpha1C/HCN2/alpha2delta channel inactivation does not require calmodulin. In contrast, beta1-subunit plays a relatively minor role in the interaction of alpha1C with HCN2. The NH(2) terminus of HCN2 and the IQ motif of alpha1C subunit are required for alpha1C/HCN2 channel interaction. Ca(2+) channel inactivation is significantly slowed in hippocampus neurons (HNs) overexpressing HCN2 mutant lacking NH(2) terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2.
Lin
Yen-Chang
YC
Center for Cardiovascular and Respiratory Sciences, West Virginia Univ. School of Medicine, Morgantown, 26506, USA.
Huang
Jianying
J
Zhang
Qi
Q
Hollander
John M
JM
Frisbee
Jefferson C
JC
Martin
Karen H
KH
Nestor
Casey
C
Goodman
Robert
R
Yu
Han-Gang
HG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D015221:Potassium Channels; D021122:Protein Subunits; D051381:Rats; D015398:Signal Transduction
D020746:Calcium Channels, L-Type; C578710:HCN2 protein, human; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; C419385:L-type calcium channel alpha(1C); D015221:Potassium Channels; D021122:Protein Subunits; D002118:Calcium