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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL071365-02
Application #
6640482
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Commarato, Michael
Project Start
2002-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$48,148
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Proenza, Catherine; Yellen, Gary (2006) Distinct populations of HCN pacemaker channels produce voltage-dependent and voltage-independent currents. J Gen Physiol 127:183-90
Shin, Ki Soon; Maertens, Chantal; Proenza, Catherine et al. (2004) Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage. Neuron 41:737-44