title: Contribution of small conductance K+channels to sinoatrial node pacemaker activity: insights from atrial-specific Na+/Ca2+exchange knockout mice.
abstract: Repolarizing currents through K+channels are essential for proper sinoatrial node (SAN) pacemaking, but the influence of intracellular Ca2+on repolarization in the SAN is uncertain. We identified all three isoforms of Ca2+-activated small conductance K+(SK) channels in the murine SAN. SK channel blockade slows repolarization and subsequent depolarization of SAN cells. In the atrial-specific Na+/Ca2+exchanger (NCX) knockout mouse, cellular Ca2+accumulation during spontaneous SAN pacemaker activity produces intermittent hyperactivation of SK channels, leading to arrhythmic pauses alternating with bursts of pacing. These findings suggest that Ca2+-sensitive SK channels can translate changes in cellular Ca2+into a repolarizing current capable of modulating pacemaking. SK channels are a potential pharmacological target for modulating SAN rate or treating SAN dysfunction, particularly under conditions characterized by abnormal increases in diastolic Ca2+.
  
  
  
  Small conductance K+(SK) channels have been implicated as modulators of spontaneous depolarization and electrical conduction that may be involved in cardiac arrhythmia. However, neither their presence nor their contribution to sinoatrial node (SAN) pacemaker activity has been investigated. Using quantitative PCR (q-PCR), immunostaining and patch clamp recordings of membrane current and voltage, we identified all three SK isoforms (SK1, SK2 and SK3) in mouse SAN. Inhibition of SK channels with the specific blocker apamin prolonged action potentials (APs) in isolated SAN cells. Apamin also slowed diastolic depolarization and reduced pacemaker rate in isolated SAN cells and intact tissue. We investigated whether the Ca2+-sensitive nature of SK channels could explain arrhythmic SAN pacemaker activity in the atrial-specific Na+/Ca2+exchange (NCX) knockout (KO) mouse, a model of cellular Ca2+overload. SAN cells isolated from the NCX KO exhibited higher SK current than wildtype (WT) and apamin prolonged their APs. SK blockade partially suppressed the arrhythmic burst pacing pattern of intact NCX KO SAN tissue. We conclude that SK channels have demonstrable effects on SAN pacemaking in the mouse. Their Ca2+-dependent activation translates changes in cellular Ca2+into a repolarizing current capable of modulating regular pacemaking. This Ca2+dependence also promotes abnormal automaticity when these channels are hyperactivated by elevated Ca2+. We propose SK channels as a potential target for modulating SAN rate, and for treating patients affected by SAN dysfunction, particularly in the setting of Ca2+overload.
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Torrente
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Zaini
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kim
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, 650 Charles Young Drive South, Los Angeles, CA, 90095-1751, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
authors.forename: Joshua I
authors.identifier: 0000-0001-8413-5719
authors.initials: JI
authors.lastname: Goldhaber
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D051640:Small-Conductance Calcium-Activated Potassium Channels; D019831:Sodium-Calcium Exchanger; D001030:Apamin; D002118:Calcium
keywords: Na+/Ca2+ exchange; sinoatrial node; small conductance K+ channels