Grant: $379,185 - National Institutes of Health - Jul. 16, 2009
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Award Description: A-kinase anchoring proteins (AKAPs) organize numerous intracellular signaling pathways by bringing together their molecular components into discrete sub-cellular microdomains. One such AKAP, AKAP79/150 interacts with protein kinase A, protein kinase C (PKC), calmodulin (CaM), calcineurin, and phosphatidylinositol 4,5- bisphosphate (PIP2), along with effectors such as M-type (KCNQ, Kv7) K+ channels and certain G protein- coupled receptors. In this project, we will study which KCNQ1-5 subunits are targets of AKAP79/150, and which Gq/11-coupled receptors of sympathetic and nodose ganglia neurons (muscarinic M1, bradykinin B2, angiotensin AT1 and purinergic P2Y) use AKAP79/150 to modulate M-type channels. We will also investigate the interactions between the CaM and PIP2 molecules with AKAP79/150 that are critical to the function of both M channels and AKAP79/150. The role of AKAP79/150 in Gq/11-coupled receptor control of neuronal discharge properties of the neurons, and on their release of neurotransmitter will be explored, both at the single-cell level, and via an in vitro model of the chronotropic response of cardiomyocytes to sympathetic neuron activity. We will use a heterologous expression system in which M-channels, receptors and signaling molecules are expressed in Chinese hamster ovary (CHO) cells, preparations of rat and mouse superior cervical ganglia (SCG) and nodose ganglia (NG) neurons, and a co-culture of SCG neurons and ventricular cardiomyocytes. Techniques to be used include fluorescence resonance energy transfer (FRET), total internal reflection fluorescence (TIRF), confocal microscopy, patch-clamp electrophysiology, carbon-fiber amperometry and video imaging. We aspire to discover the mechanisms endowing AKAP79/150 in specificity towards receptors and M-type K+ channels, and its functional role in shaping the neurophysiological and neurotransmitter release properties of neurons. PUBLIC HEALTH RELEVANCE: The signaling pathways that comprise a common motif in biological signaling underlie how the nervous system is regulated, including alterations in emotional state and mood, personality and the acquisition and use of memories. We will study the regulation of the M-type potassium ion channel, which plays dominant role in regulation of nerve-cell excitability, mediated by the A-kinase Anchoring Protein, AKAP79/150. The elucidation of the mechanisms and functional role of AKAP79/150 in M-channel activity will shed light on how the nervous system functions in health and disease.
Project Description: The brain works using a combination of electrical and chemical signals that underlie all the processes of nerve cells, including thought, mood, movement, consciousness, and learning and memory. The electrical signals are made by salt atoms passing in and out of nerve cells through specialized proteins called ion channels. The chemical signals consist of a family of neurotransmitter and hormone molecules that bind to specific receptors on the cells, causing the electrical signal to ?jump the gap? between nerve cells, or modulating the ion channels which underlie electrical activity. The modulation is organized into signaling pathways, consisting of intracellular molecules that communicate the signal from receptor binding to intracellular action. These pathways shape brain activity, resulting in changes in mood or emotional state, regulation of the heart rate and blood pressure, and the consolidation of new memories. Dysfunction in the ion channels, or in the chemical signals that regulate them, result in syndromes of epilepsy, movement and memory disorders, cardiovascular malfunction and psychiatric disease. Thus, their study should help in novel modes of therapeutic treatments for these human diseases. Recent work indicates that these complex signaling cascades are orchestrated by ?scaffolding proteins? called A-kinase anchoring proteins (AKAPs). This project studies the physiology and mechanisms of one such AKAP, called AKAP79/150, that associates with a potassium ion channel called the ?M channel,? so named for its modulation by stimulation of muscarinic acetylcholine receptors on nerve cells. The project will investigate which M channels are targets of AKAP79/150, which neurotransmitter/hormone receptors use AKAP79/150 in the signaling pathways that regulate M-channel activity, the mechanism by which AKAP79/150 acts inside cells, and the functional role of AKAP79/150 in controlling nerve cell excitability.
Jobs Summary: Prime recipient retained Associate Professor, Postdoctoral Fellow, Teaching Assistant, and Research Associate. Prime recipient created Research Associate. (Total jobs reported: 3)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 16, 2009. Help expand these official descriptions using the wiki below.