Molecular mechanisms of adrenergic stimulation in the heart

Abstract

Increased cardiac output in response to beta-adrenergic receptor stimulation is achieved by rapid alteration of the activity of cardiac ion channels, pumps, and exchangers. Over the past decade, the discovery of macromolecular complexes, which include the ion channels and pumps and the kinases that control their level of phosphorylation, has led to an increased understanding of the molecular mechanisms behind the cardiac adrenergic response. The increased understanding has led to the discovery of a new long QT gene encoding an accessory protein in one of these macromolecular complexes. This article briefly reviews the major components of the beta-adrenergic pathway in the heart and discusses the direction of current and future research.

Figure 1

A schematic representation of the major electrophysiological determinants of adrenergic response in cardiac myocytes. Catecholaminergic stimulation of β-receptors leads to increases in cAMP and PKA. Cyclic nucleotide binding to the HCN channels increases intrinsic pacing rate of nodal cells. PKA phosphorylation upregulates several targets in the Ca²⁺ signaling cascade to increase contractile force and the I_Ks channel to abbreviate the action potential duration to compensate for the increased heart rate.

Figure 2

A schematic diagram of the I_Ks macromolecular complex. I_Ks channels are comprised of α-(KCNQ1) and β-(KCNE1) subunits with a PKA phosphorylation on the N-terminus of KCNQ1 at position 27. The AKAP Yotiao (AKAP9) has a functionally important phosphorylation site at position 43 and interacts with the c-terminus of KCNQ1 to recruit several key enzymes, including PKA, PP1, and PDE4, to the channel complex.