Cardiac ion channels and tobacco-related disease
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: 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.