Regulation of cAMP production requires an elaborate series of signaling molecules that are currently used as targets for drug intervention in the treatment of heart disease, hypertension, Schizophrenia, Parkinson's, asthma, chronic pain, and many more. Despite being a fundamental """"""""second messenger"""""""" in a huge array of important physiological processes and pathophysiological conditions, the molecular mechanisms that control the specificity and temporal aspects of cAMP actions are not well understood. The discovery of a large and complex family of proteins termed AKAPs likely play a major role in this regulation. AKAPs had originally been thought of as anchoring the cAMP-dependent protein kinase A (PKA), to downstream targets of cAMP/PKA actions. However, in recent studies we have found that several isoforms of the enzyme that produces cAMP, adenylyl cyclase (AC) are also found in complex with several AKAPs in both brain and heart, suggesting that the production of cAMP as well its downstream targets are co-localized. Further, we have found evidence that the upstream regulators of AC, heterotrimeric G proteins, are also a part of an AC complex through their binding to previously unrecognized sites on AC. This application seeks to understand how macromolecular complexes containing AC gives rise to dynamic and specific regulation of cAMP-controlled downstream events, such as ion channels involved in inflammatory pain and glutamate receptors modulating hippocampal synaptic activity.
Three specific aims are designed to address the hypothesis that, signaling complexes containing ACs are required for spatial and temporal regulation of cAMP-dependent processes.
Aim 1 will establish the function of pre-formed complexes of AC and heterotrimeric G proteins, Aim 2 will determine how AKAPs regulate AC activity and dynamics, and Aim 3 will determine the requirement of bound AC for AKAP function.
Regulation of cAMP production requires an elaborate series of signaling molecules that are currently used as targets for drug intervention in the treatment of heart disease, hypertension, Schizophrenia, Parkinson's, asthma, chronic pain, and many more. Despite being a fundamental signaling molecule in physiological and pathophysiological conditions, the molecular mechanisms that control the specificity and temporal aspects of cAMP actions are not completely understood. This is particularly true for the enzyme that produces cAMP, adenylyl cyclase (AC). We have identified novel multi-protein complexes containing AC that control cAMP signaling in both brain and heart. The existence of these complexes suggests that the production of cAMP as well its downstream targets are co- localized. In addition, the combinations of specific AC isoforms and targets of cAMP actions are far more organized than previously appreciated. This application seeks to understand how macromolecular complexes containing AC gives rise to cAMP regulation and specificity, and to investigate the roles of these complexes in controlling processes involved in inflammatory pain and hippocampal synaptic regulation.
|Bavencoffe, Alexis; Li, Yong; Wu, Zizhen et al. (2016) Persistent Electrical Activity in Primary Nociceptors after Spinal Cord Injury Is Maintained by Scaffolded Adenylyl Cyclase and Protein Kinase A and Is Associated with Altered Adenylyl Cyclase Regulation. J Neurosci 36:1660-8|
|Yakubovich, Daniel; Berlin, Shai; Kahanovitch, Uri et al. (2015) A Quantitative Model of the GIRK1/2 Channel Reveals That Its Basal and Evoked Activities Are Controlled by Unequal Stoichiometry of GÎ± and GÎ²Î³. PLoS Comput Biol 11:e1004598|
|Brand, Cameron S; Sadana, Rachna; Malik, Sundeep et al. (2015) Adenylyl Cyclase 5 Regulation by GÎ²Î³ Involves Isoform-Specific Use of Multiple Interaction Sites. Mol Pharmacol 88:758-67|
|Xie, Keqiang; Masuho, Ikuo; Shih, Chien-Cheng et al. (2015) Stable G protein-effector complexes in striatal neurons: mechanism of assembly and role in neurotransmitter signaling. Elife 4:|
|Farhy Tselnicker, Isabella; Tsemakhovich, Vladimir; Rishal, Ida et al. (2014) Dual regulation of G proteins and the G-protein-activated K+ channels by lithium. Proc Natl Acad Sci U S A 111:5018-23|
|Dvir, Meidan; Strulovich, Roi; Sachyani, Dana et al. (2014) Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIPâ‚‚. J Cell Sci 127:3943-55|
|Kahanovitch, Uri; Tsemakhovich, Vladimir; Berlin, Shai et al. (2014) Recruitment of GÎ²Î³ controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1. J Physiol 592:5373-90|
|Efendiev, Riad; Bavencoffe, Alexis; Hu, Hongzhen et al. (2013) Scaffolding by A-kinase anchoring protein enhances functional coupling between adenylyl cyclase and TRPV1 channel. J Biol Chem 288:3929-37|
|Scott, John D; Dessauer, Carmen W; Tasken, Kjetil (2013) Creating order from chaos: cellular regulation by kinase anchoring. Annu Rev Pharmacol Toxicol 53:187-210|
|Brand, Cameron S; Hocker, Harrison J; Gorfe, Alemayehu A et al. (2013) Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds. J Pharmacol Exp Ther 347:265-75|
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