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Cardiac ion channels and tobacco-related disease

Institution: University of California, Santa Barbara
Investigator(s): Carol Vandenberg, Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0114 Award: $389,983
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco smoking is the leading preventable cause of death in the United States and is an important cause of coronary heart disease. The effects of smoking on the cardiovascular system include an acute increase in blood pressure and decrease in oxygen delivery. Smoking is a strong risk factor in cardiovascular diseases that include arrhythmia, hypertension, myocardial infarction, stroke and ischemic heart disease. Both smokers as well as non-smokers who are exposed to secondhand smoke are at increased risk of cardiac disease.

The mechanism by which smoking causes harmful effects on the cardiovascular system are beginning to be understood. Cigarette smoking activates the sympathetic nervous system in humans, causing an increase in blood pressure and heart rate. Cardiac sympathetic nerves also play an important role in regulating coronary blood flow. Nicotine appears to be the primary component of tobacco that gives rise to cardiovascular stimulation leading to elevated blood pressure and heart rate, and increases the likelihood of cardiac arrhythmia.

How does tobacco use cause disease in the heart? We are exploring the hypothesis that one mechanism that nicotine increases the risk of cardiovascular disease is by its effects on potassium channels in the heart and blood vessels. Potassium channels are proteins in the cell membrane that determine the flux of potassium ions into and out of the cell. Potassium channels are key regulators of electrical activity in the heart and vasculature. In the heart, they control the duration of the cardiac action potential, mediate the repolarization phase of the action potential, and set the membrane resting potential. They have been implicated in the cause and control of cardiac arrhythmia because of their central role in regulation of electrical activity. Indeed, Class III anti-arrhythmic drugs are targeted to cardiac potassium channels. Potassium channels also have been implicated in control of blood pressure. Potassium channel opener drugs are used to control hypertension through their direct interaction with potassium channels in blood vessels.

Recently we have discovered that an important class of potassium channels in the heart, inward rectifier potassium channels, are bound to a complex of scaffolding proteins, including synapse-associated protein 97 (SAP97). Scaffolding proteins are multi-functional proteins that organize signaling complexes, and are involved in regulation of channel electrical activity, channel localization and clustering within cells. Importantly, we found in the heart that binding of the inward rectifier potassium channels to SAP97 is dynamically regulated by a cellular signaling pathway that is stimulated by nicotine. Within minutes of stimulation with a drug that mimics sympathetic stimulation (the downstream effect of nicotine), inward rectifier potassium channels are no longer able to associate with SAP97.

We are investigating the physiological consequences of potassium channel association with scaffolding proteins, and the regulation of that interaction by pathways that are stimulated by nicotine. We are testing the hypothesis that the interaction of cardiac potassium channels with intracellular scaffolding proteins acts to regulate the activity, localization and turnover of the channels in the heart, which will shed light on the mechanism by which nicotine is associated with cardiac arrhythmia and hypertension. We anticipate that an understanding of the control of cardiovascular responses that are altered by nicotine may open up new targets for therapeutic intervention in the treatment of tobacco-related disease.
Publications

Proteomic identification of multi-protein complex associated with inward rectifier potassium Kir2 channel.
Periodical: Biophysical Journal Index Medicus:
Authors: Leonoudakis D, Anderson S, Yates JR, Vandenberg CA ABS
Yr: 2002 Vol: 84 Nbr: Abs: Pg: 224a

A multi-protein complex of SAP97, CASK, Veli and Mint1 is associated with inward rectifier Kir2 potassium channels.
Periodical: Biophysical Journal Index Medicus:
Authors: Leonoudakis D, Radeke CM, Conti LR, Vandenberg CA ABS
Yr: 2002 Vol: 84 Nbr: Abs: Pg: 225a

Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x) associated proteins.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Leonoudakis D, Conti LR, Anderson S, Radeke CM, McGuire LMM, Adams ME, Vandenberg C, et al ART
Yr: 2004 Vol: 279 Nbr: Abs: Pg: 22331-22346

A multi-protein trafficking complex composed of SAP97, CASK, Veli and Mint1 is associated with inward rectifier Kir2 potassium channels.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Leonoudakis D, Conti LR, Radeke CM, McGuire LMM, Vandenberg C ART
Yr: 2004 Vol: 279 Nbr: Abs: Pg: 19051-10963

Proteomic identification of multi-protein complexes associated with inward rectifier potassium Kir2 channels.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Leonoudakis D, Conti L, Anderson S, Radeke CM, Yates JR, Vandenberg CA ABS
Yr: 2003 Vol: Nbr: Abs: 685.15 Pg:

Cholesterol sensitivity and lipid raft targeting of kir 2.1 channels.
Periodical: Biophysical Journal Index Medicus:
Authors: Romanenko VG, Fang Y, Byfield F, Travis AJ, Vandenberg CA, Rothblat GH, Levitan I ART
Yr: 2004 Vol: 87 Nbr: Abs: Pg: 3850 - 3861

ERA dication of ion channels destined for the plasma membrane. Focus on a role of the ubiquitin-proteasome degradation pathway in the biogenesis efficiency of beta-cell ATP- sensitive potassium channels.
Periodical: American journal of physiology. Cell physiology Index Medicus:
Authors: Conti LR, Vandenberg CA ART
Yr: 0 Vol: Nbr: Abs: Pg:

Functional expression of Kir2x in human aortic endothelial cells: the dominant role of Kir2.2.
Periodical: American journal of physiology. Cell physiology Index Medicus:
Authors: Fang Y, Schram G, Robanenko V, Shi C, Conti L, Vandenberg CA, et al ART
Yr: 0 Vol: Nbr: Abs: Pg: