A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+–cAMP–protein kinase A (PKA) signaling regulated clock coupling. When these clocks became uncoupled, SANCs failed to generate spontaneous action potentials, showing a depolarized membrane potential and disorganized local Ca2+ releases that failed to activate the M clock. β-Adrenergic receptor (β-AR) stimulation, which increases cAMP concentrations and clock coupling in other species, restored spontaneous, rhythmic action potentials in some nonbeating "arrested" human SANCs by increasing intracellular Ca2+ concentrations and synchronizing diastolic local Ca2+ releases. When β-AR stimulation was withdrawn, the clocks again became uncoupled, and SANCs reverted to a nonbeating arrested state. Thus, automaticity of human pacemaker cells is driven by a c...

Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Tsutsui, K., Monfredi, O. J., Sirenko-Tagirova, S. G., Maltseva, L. A., Bychkov, R., Kim, M. S., Ziman, B. D., Tarasov, K. V., Tarasova, Y. S., Zhang, J., Wang, M., Maltsev, A. V., Brennan, J. A., Efimov, I. R., Stern, M. D., Maltsev, V. A., Lakatta, E. G Tags: STKE Research Articles Source Type: news