DIRECT ACTIVATION OF CARDIAC-PACEMAKER CHANNELS BY INTRACELLULAR CYCLIC-AMP

CYCLIC AMP acts as a second messenger in the modulation of several ion channels 1-9 that are typically controlled by a phosphorylation process 10. In cardiac pacemaker cells, adrenaline and acetylcholine regulate the hyperpolarization-activated current (i(f)), but in opposite ways; this current is involved in the generation and modulation of pacemaker activity 11. These actions are mediated by cAMP and underlie control of spontaneous rate by neurotransmitters 12-17. Whether the cAMP modulation of i(f) is mediated by channel phosphorylation is, however, still unknown. Here we investigate the action of cAMP on i(f) in excised patches of cardiac pacemaker cells and find that cAMP activates i(f) by a mechanism independent of phosphorylation, involving a direct interaction with the channels at their cytoplasmic side. Cyclic AMP activates i(f) 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.