Pacemaker potential

Abstract: CYCLIC AMP acts as a second messenger in the modulation of several ion channels1–9 that are typically controlled by a phosphorylation process10. In cardiac pacemaker cells, adrenaline and acetylcholine regulate the hyperpolarization-activated current (if), but in opposite ways; this current is involved in the generation and modulation of pacemaker activity11. These actions are mediated by cAMP and underlie control of spontaneous rate by neurotransmitters12–17. Whether the cAMP modulation of if is mediated by channel phosphorylation is, however, still unknown. Here we investigate the action of cAMP on if in excised patches of cardiac pacemaker cells and find that cAMP activates if by a mechanism independent of phosphorylation, involving a direct interaction with the channels at their cytoplasmic side. Cyclic AMP activates if by shifting its activation curve to more positive voltages, in agreement with whole-cell results. This is the first evidence of an ion channel whose gating is dually regulated by voltage and direct cAMP binding.

Abstract: Major topics addressed in this review on cardiac pacemaking in the sinoatrial node are; 1) isolated pacemaker cells; 2) membrane currents of sinoatrial node cells; 3) mechanism of pacemaking; 4) regulation of pacemaker currents

Abstract: Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca(2+) releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca(2+) clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca(2+) clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca(2+), and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.

Abstract: THE way in which adrenaline acts on the sinoatrial (SA) node to accelerate the heart rate has hitherto been obscure. However, in various other parts of the heart adrenaline increases the slow inward (Ca2+/Na+) current1–4, and voltage-recording experiments have indicated that adrenaline also has this action in the sinus region5–7. In the voltage-clamp experiments reported here, we find that adrenaline does indeed increase the slow inward current in the SA node of the rabbit, but that it also augments the outward current which would tend to decelerate pacemaker depolarisation. We find that an additional current, if, is activated within the range of voltage where the pacemaker depolarisation occurs: this could be important both in normal pacemaking and in adrenaline-induced acceleration.