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(Circulation Research. 2006;98:437.)
© 2006 American Heart Association, Inc.

Editorials

A Novel Mechanism of Pacemaker Control That Depends on High Levels of cAMP and PKA-Dependent Phosphorylation

A Precisely Controlled Biological Clock

John H.B. Bridge, Christopher J. Davidson, Eleonora Savio-Galimberti

From The Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City.

Correspondence to John H.B. Bridge, PhD, Research Professor of Internal Medicine, The Nora Eccles Harrison, Cardiovascular Research and Training Institute (CVRTI), University of Utah, 95 S 2000 E Back, Salt Lake City, UT. E-mail bridge@cvrti.utah.edu

See related article, pages 505–514

Key Words: local calcium release • sarcoplasmic reticulum • Na–Ca exchanger • ryanodine receptor • diastolic depolarization

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
The mammalian heart has remarkable intrinsic rhythmic properties. It is widely agreed that spontaneous diastolic depolarizations (DDs) in sino-atrial node cells (SANCs) periodically initiate action potentials (AP), which set the rhythm of the heart.¹ Efforts to understand the origin of the pacemaker activity have a lengthy history and the subject has, for various technical reasons, proved somewhat intractable.

Any explanation of pacemaker activity must address three central issues. First, how do DDs arise? Second, what determines their periodicity? And third, how is the rate modulated? In this issue of Circulation Research, Vinogradova and her colleagues² offer some novel observations that go far toward explaining these issues. The article, which is the most recent of an exhaustive series of experiments from Dr Lakatta’s group, offers an explanation of the control of pacemaker activity based on both biophysical and biochemical observations, integrated with appropriate mathematical modeling (see supplement). This work depends on the central idea that pacemaking involves complex interactions within a multi-molecular complex that resides in both sarcolemmal and SR membranes. An attractive feature of this work is that it suggests a number of interesting structural and functional avenues of investigation that are amenable to contemporary biophysical methods, particularly confocal microscopy.

No single current by itself is responsible for DD. It is the sum of at least 6 ionic currents: I_kr, I_f, I_st, I_Ca (with two components: I_Ca-T and I_Ca-L), and I_NCX.^1,3 In a previous study, Bogdanov et al⁴ show that sodium–calcium exchanger (NCX) is . . . [Full Text of this Article]

Related Article:

High Basal Protein Kinase A–Dependent Phosphorylation Drives Rhythmic Internal Ca²⁺ Store Oscillations and Spontaneous Beating of Cardiac Pacemaker Cells

Tatiana M. Vinogradova, Alexey E. Lyashkov, Weizhong Zhu, Abdul M. Ruknudin, Syevda Sirenko, Dongmei Yang, Shekhar Deo, Matthew Barlow, Shavsha Johnson, James L. Caffrey, Ying-Ying Zhou, Rui-Ping Xiao, Heping Cheng, Michael D. Stern, Victor A. Maltsev, and Edward G. Lakatta
Circ. Res. 2006 98: 505-514. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				V. A. Maltsev and E. G. Lakatta Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H594 - H615. [Abstract] [Full Text] [PDF]