Phospholemman modulates the gating of cardiac L-type calcium channels.
Ca(2+) entry through L-type calcium channels (Ca(V)1.2) is critical in shaping the cardiac action potential and initiating cardiac contraction. Modulation of Ca(V)1.2 channel gating directly affects myocyte excitability and cardiac function. We have found that phospholemman (PLM), a member of the FXYD family and regulator of cardiac ion transport, coimmunoprecipitates with Ca(V)1.2 channels from guinea pig myocytes, which suggests PLM is an endogenous modulator. Cotransfection of PLM in HEK293 cells slowed Ca(V)1.2 current activation at voltages near the threshold for activation, slowed deactivation after long and strong depolarizing steps, enhanced the rate and magnitude of voltage-dependent inactivation (VDI), and slowed recovery from inactivation. However, Ca(2+)-dependent inactivation was not affected. Consistent with slower channel closing, PLM significantly increased Ca(2+) influx via Ca(V)1.2 channels during the repolarization phase of a human cardiac action potential waveform. Our results support PLM as an endogenous regulator of Ca(V)1.2 channel gating. The enhanced VDI induced by PLM may help protect the heart under conditions such as ischemia or tachycardia where the channels are depolarized for prolonged periods of time and could induce Ca(2+) overload. The time and voltage-dependent slowed deactivation could represent a gating shift that helps maintain Ca(2+) influx during the cardiac action potential waveform plateau phase.
Wang
Xianming
X
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Gao
Guofeng
G
Guo
Kai
K
Yarotskyy
Viktor
V
Huang
Congxin
C
Elmslie
Keith S
KS
Peterson
Blaise Z
BZ
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007477:Ions; D007511:Ischemia / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013610:Tachycardia / Q000473:pathology
D020746:Calcium Channels, L-Type; D007477:Ions; D008565:Membrane Proteins; D010750:Phosphoproteins; C069141:phospholemman; D002118:Calcium