Abstract
The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by “funny” current (If) through HCN4 channels (the “Membrane Clock“ hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two (“Coupled Clock”). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN.
Highlights
Sinus node disease is associated with death from severe bradycardia
KO mice survived into adulthood despite the complete absence of NCX1 in the atrium as measured directly by immunoblots from atrial homogenates probed with a well-characterized NCX1 antibody (Fig. 1A)
The role of NCX as a critical participant in the genesis of cardiac sinoatrial node (SAN) pacemaker activity through either a Ca-clock or a Coupled-clock mechanism is controversial [4]. This concept departs from the prevailing hypothesis of pacemaker function for the last 20 years, which has revolved around the so-called ‘‘funny current’’ (If) through hyperpolarization-activated cyclic nucleotidesensitive (HCN) channels [2]
Summary
Sinus node disease is associated with death from severe bradycardia. It is associated with a high incidence of supraventricular tachycardia and accounts for approximately half of the 370,000 pacemakers implanted in the United States in 2010 at an average cost of $65,538 and totaling $24B [1]. The mechanism underlying spontaneous pacemaker activity in the sinoatrial node (SAN) is uncertain. In the M clock model, If current activates when the SAN cell repolarizes to its resting membrane potential. Inward If depolarizes the cell in diastole until the threshold is reached for activation of the L-type Ca current (ICa), which triggers an action potential (AP). The response of heart rate in patients to If-specific drugs parallels cellular studies, supporting the relevance of If and the M clock to pacemaker activity
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