Direct activation of cardiac pacemaker channels by intracellular cyclic AMP

Abstract

Cyclic AMP acts as a second messenger in the modulation of several ion channels that are typically controlled by a phosphorylation process. 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 activity. These actions are mediated by cAMP and underlie control of spontaneous rate by neurotransmitters. 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.

Regulation of the beta‐stimulation of the Na(+)‐K+ pump current in guinea‐pig ventricular myocytes by a cAMP‐dependent PKA pathway.

“…Several reports indicate that activated G8 protein may mediate a phosphorylation-independent influence on certain membrane ion conductances (Yatani, Codina, Imoto, Reeves, Birnbaumer & Brown, 1987;Schubert, VanDongen, Kirsch & Brown, 1989;Yatani, Okabe, Codina, Birnbaumer & Brown, 1990). Intracellular cAMP has been suggested as directly activating cardiac pacemaker channels (DiFrancesco & Tortora, 1991). It is therefore necessary to know whether G8 or cAMP have directly affected f,-adrenergic stimulation of Ip.…”

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

“…HR as well as I f current are directly modulated by sympathetic and parasympathetic activities (DiFrancesco et al, 1989;DiFrancesco & Tortora, 1991;Guth & Dietze, 1995). It has been shown that I f current of sinoatrial node pacemaker cells is affected by adrenergic stimulation (DiFrancesco & Tortora, 1991) and that ivabradine is a usedependent I f current blocker (Bois et al, 1996;Bucchi et al, 2002).…”

“…It has been shown that I f current of sinoatrial node pacemaker cells is affected by adrenergic stimulation (DiFrancesco & Tortora, 1991) and that ivabradine is a usedependent I f current blocker (Bois et al, 1996;Bucchi et al, 2002). Therefore, it is expected that the efficacy of ivabradine on HR would be modulated by alterations in the sympathetic activity.…”

Hyperpolarization-Activated Current (I h) in Vestibular Calyx Terminals: Characterization and Role in Shaping Postsynaptic Events

“…Cyclic nucleotides interact directly with HCN channels through a C-terminal cyclic nucleotide binding domain (CNBD). cAMP increases conductance and shifts I h voltage dependence to more depolarized potentials (DiFrancesco and Tortora 1991). I h may influence integration of postsynaptic events by calibrating membrane resting potential and controlling membrane resistance.…”