title: Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes.
abstract: Voltage-gated Na(+) channels are critical determinants of electrophysiological properties in the heart. Stimulation of beta-adrenergic receptors, which activate cAMP-dependent protein kinase (protein kinase A [PKA]), can alter impulse conduction in normal tissue and promote development of cardiac arrhythmias in pathological states. Recent studies demonstrate that PKA activation increases cardiac Na(+) currents, although the mechanism of this effect is unknown. To explore the molecular basis of Na(+) channel modulation by beta-adrenergic receptors, we have examined the effects of PKA activation on the recombinant human cardiac Na(+) channel, hH1. Both in the absence and the presence of hbeta(1) subunit coexpression, activation of PKA caused a slow increase in Na(+) current that did not saturate despite kinase stimulation for 1 hour. In addition, there was a small shift in the voltage dependence of channel activation and inactivation to more negative voltages. Chloroquine and monensin, compounds that disrupt plasma membrane recycling, reduced hH1 current, suggesting rapid turnover of channels at the cell surface. Preincubation with these agents also prevented the PKA-mediated rise in Na(+) current, indicating that this effect likely resulted from an increased number of Na(+) channels in the plasma membrane. Experiments using chimeric constructs of hH1 and the skeletal muscle Na(+) channel, hSKM1, identified the I-II interdomain loop of hH1 as the region responsible for the PKA effect. These results demonstrate that activation of PKA modulates both trafficking and function of the hH1 channel, with changes in Na(+) current that could either speed or slow conduction, depending on the physiological circumstances.
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Yi
authors.forename: N
authors.initials: N
authors.lastname: Hu
authors.forename: A L
authors.initials: AL
authors.lastname: George
authors.forename: K T
authors.initials: KT
authors.lastname: Murray
mesh_terms: D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D008985:Monensin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D011994:Recombinant Proteins; D015222:Sodium Channels / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D011994:Recombinant Proteins; D015222:Sodium Channels; D002738:Chloroquine; D008985:Monensin; D017868:Cyclic AMP-Dependent Protein Kinases