How is the heart rate regulated in the sinoatrial node? Another piece to the puzzle

Part of the sympathetic flight-or-fight response is an increase in intracellular cyclic AMP (cAMP) that raises the rate of action potential generation in the heart pacemaker, the sinoatrial (SA) node (Robinson and Siegelbaum, 2003). The increased firing rate in the SA node increases the heart rate and cardiac output necessary to deliver more oxygen and nutrients to the muscles for the flight-or-fight response. How cAMP increases the rate of the SA node has been debated for a long time. Recently, there has been a hot debate between groups promoting a model in which hyperpolarization-activated cyclic nu-cleotide–gated (HCN) channels are the main regulator of the heart rate, and groups promoting a model in which intracellular Ca 2+ oscillations affecting currents through Na + /Ca 2+ exchangers are the main regulator of the heart rate (Lakatta and DiFrancesco, 2009). There are several candidate targets for the increased cAMP in the SA node during sympathetic stimulation (Fig. 1). For example, cAMP-activated protein kinases (PKA) have been shown to phosphorylate ryanodine receptors and other Ca 2+-cycling proteins in the SA node, leading to altered calcium cycles and increased diastolic currents through Na + /Ca 2+ exchangers (Lakatta et al., 2010). In contrast, HCN channels have earlier been shown to be directly modulated by cAMP in the SA node by a mechanism that is independent of PKA activation (DiFrancesco and Tortora, 1991). In this issue, Liao et al. show that HCN channels in the SA node are also modulated by PKA, and suggest that this PKA modulation of HCN channels might contribute to the increased firing rate in the SA node in response to sympathetic stimulation. In addition , the result that PKA directly phosphorylates HCN channels might further reduce some of the confusion in the field regarding how sympathetic stimulation affects heart rate, as PKA and HCN channels were previously thought to act through different pathways in the SA node to increase the heart rate. HCN channels are also called pacemaker channels due to their presumed effect on the cardiac heart rate (Robinson and Siegelbaum, 2003). There are four members in the mammalian HCN channel family: HCN1–4 (Robinson and Siegelbaum, 2003). HCN4 is the most prevalent in the SA node, but HCN1 and HCN2 have also been found in the SA node in some species (Moroni et al., 2001). HCN channels belong to the superfamily of voltage-gated ion channels. HCN channels are tetra-meric channels …