title: Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.
abstract: The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I(K1)-I(Na) interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I(K1)-I(Na) interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na(V)1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the post synaptic density, discs large, and zonula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na(v)1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na(v)1.5-Kir2.1 interactions. The reciprocal modulation between Na(v)1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.
authors.affiliation: Departments of Internal Medicine, Molecular and Integrative Physiology, and Pharmacology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48108, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Milstein
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.forename: Daniela Ponce
authors.initials: DP
authors.lastname: Balbuena
authors.forename: Justus M B
authors.initials: JM
authors.lastname: Anumonwo
authors.forename: David S
authors.initials: DS
authors.lastname: Auerbach
authors.forename: Philip B
authors.initials: PB
authors.lastname: Furspan
authors.forename: Luqia
authors.initials: L
authors.lastname: Hou
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Schumacher
authors.forename: Ravi
authors.initials: R
authors.lastname: Vaidyanathan
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Martens
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology; D000074288:Discs Large Homolog 1 Protein; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D062826:Zonula Occludens-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; C501119:Dlg1 protein, rat; C489461:Kir2.1 channel; D008565:Membrane Proteins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010750:Phosphoproteins; D024661:Potassium Channels, Inwardly Rectifying; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D051528:Guanylate Kinases