title: Burst pacemaker activity of the sinoatrial node in sodium-calcium exchanger knockout mice.
abstract: In sinoatrial node (SAN) cells, electrogenic sodium-calcium exchange (NCX) is the dominant calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent. Voltage mapping revealed disorganized and arrhythmic depolarizations within the NCX KO SAN that failed to propagate into the atria. LSCM revealed intermittent bursts of Ca transients. Bursts were accompanied by rising diastolic Ca, culminating in long pauses dominated by Ca waves. The L-type Ca channel agonist BayK8644 reduced the rate of Ca transients and inhibited burst generation in the NCX KO SAN whereas the Ca buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl ester) (BAPTA AM) did the opposite. These results suggest that cellular Ca accumulation hinders spontaneous depolarization in the NCX KO SAN, possibly by inhibiting L-type Ca currents. The funny current (If) blocker ivabradine also suppressed NCX KO SAN automaticity. We conclude that pacemaker activity is present in the NCX KO SAN, generated by a mechanism that depends upon If. However, the absence of NCX-mediated depolarization in combination with impaired Ca efflux results in intermittent bursts of pacemaker activity, reminiscent of human sinus node dysfunction and "tachy-brady" syndrome.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048;
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Torrente
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048;
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048;
authors.forename: Audrey
authors.initials: A
authors.lastname: Zaini
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048;
authors.forename: Jeanney
authors.initials: J
authors.lastname: Kang
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048;
authors.forename: Scott T
authors.initials: ST
authors.lastname: Lamp
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048; joshua.goldhaber@cshs.org.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
mesh_terms: D000200:Action Potentials; D000818:Animals; D001683:Biological Clocks; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D003971:Diastole; D004558:Electric Stimulation; D005260:Female; D005355:Fibrosis; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012849:Sinoatrial Node / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D017630:Connexins; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: arrhythmia; intracellular calcium; pacemaker activity; sinoatrial node; sodium-calcium exchange