Instantaneous current and inactivation in HCN channels

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Hyperpolarization-activated "pacemaker" currents are important for rhythmic firing in the mammalian heart and brain. This proposal addresses two previously undescribed features of pacemaker currents, (1) a voltage-independent instantaneous current, and (2) inactivation of mammalian currents. The molecular mechanisms responsible for these two current properties will be probed experimentally in heterologously- expressed pacemaker channels by a combination of molecular biology, chemical modification, and patch clamp electrophysiology. The presence of an instantaneous current would suggest that a background current accompanies expression of pacemaker channels in the heart and brain, and would raise the question of whether similar mechanisms exist in other ion channels. The hypotheses that cAMP-dependent inactivation existing in mammalian pacemarker currents and is altered by intracellular factors suggest a novel mechanism for modulation of these currents. Determination of the molecular mechanism for an instantaneous current and/or inactivation of mammalian pacemaker currents would advance our understanding of the control and modulation of spontaneous rhythmic activity in the heart and brain. Description of these channel behavior may also present opportunities for development of state-dependent pharmacological agents that act on pacemaker channels.