Heart rate as a determinant of L-type Ca2+ channel activity: mechanisms and implication in force-frequency relation.
Early studies in enzymatically isolated animal cardiomyocytes indicated that voltage-gated "L-type" Ca2+ currents (ICaL) can be upregulated following an increase of the frequency of activation. Recently, we evidenced a similar regulation of ICaL in human cardiomyocytes from both left and right ventricles and atria over a physiopathological range of stimulations (between 0.5 and 5 Hz). This regulation, enhanced by the beta-adrenergic stimulation, may be involved in the frequency-dependent potentiation of cardiac contractile force in the human healthy myocardium. We show here that the frequency-dependent regulation of ICaL is controlled by the level of phosphorylation, as well as dephosphorylation, of the Ca2+ channels. It was enhanced following activation of the protein kinase A activated by intracellular cyclic AMP (cAMP). Therefore, we anticipate that all agents stimulating cAMP production will favor this process, which was demonstrated here by activating 5HT-4 receptors using serotonin. Alternatively, it was also enhanced by the phosphatase inhibitor okadaic acid which prevents Ca2+ channels dephosphorylation. Alteration or abnormal modulation by beta-adrenergic receptor stimulation of the frequency-dependent facilitation of ICaL may partly explain the altered force-frequency relation described in heart failure.
Lemaire
S
S
Institut de Génétique Humaine, CNRS, Montpellier, France.
Piot
C
C
Leclercq
F
F
Leuranguer
V
V
Nargeot
J
J
Richard
S
S
D001696:Biomechanical Phenomena; D015220:Calcium Channels / Q000502:physiology*; D002303:Cardiac Output, Low / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D010766:Phosphorylation
D015220:Calcium Channels; D000242:Cyclic AMP