The vertebrate heart contracts spontaneously, but the force and frequency of contraction are increased by norepinephrine (NE) released from sympathetic nerves and decreased by acetylcholine (ACh) released from parasympathetic nerves. At the molecular level, these transmiters act upon several different effector systems. The effects on beat frequency are produced by modulation of several kinds of ionic channels in the plasma membrane and consequent alteration of pacemaker currents. Effects on contractile force are mediated by changes in myosin cross-bridge activity which is regulated by (1) the influx of Ca during the action potential, (2) Ca sequestration and release by the sarcoplasmic reticulum (SR), and (3) the functioning of proteins in the contractile apparatus. The molecular mechanisms underlying these effects, however, are poorly understood. The overall goal of this research is to understand the molecular mechanisms which underly neural (particularly parasympathetic) control of the heart. We would like to understand how the binding of ACh to receptors is transmitted to different effector systems (ion channels, contractile apparatus, etc.), how the different effectors contribute quantitatively to changes in contractile force and frequency, and whether the opposing effects of sympathetic and parasympathetic activity are mediated through opposite effects on the same effector systems. This research will address three specific questions. (1) What are the molecular mechanisms underlying the increase in K+ conductance (hyperpolarization) produced by ACh in the heart. Electrophysiological techniques will be used to determine the mechanisms which are responsible for the long duration of this response. (2) Does phosphorylation of the myofibrillar protein, C-protein, play a role in regulating the force of cardiac contraction? Biochemical experiments will correlate phosphorylation of this protein with contractile activity of the heart. (3) What are the molecular mechanisms by which ACh stimulates dephosphorylation of C-protein? These studies hopefully will increase our understanding of the mechanisms by which ACh regulates heartbeat.
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