Cyclic AMP is a universal second messenger and is essential for the chronotropic, inotropic and lusitropic effects during the `fight-or-flight' response. Dysregulation of cAMP signaling induces hypertrophic growth and ventricular dysfunction, eventually leading to heart failure. Adenylyl cyclase (AC) production of cAMP is controlled on many levels, including the formation of macromolecular complexes that generate localized pools of cAMP. Disorganization of cAMP compartmentation and a loss of hormonal specificity occur in models of chronic heart failure, suggesting a mechanism for the cardiotoxic effects of the cAMP pathway. We have previously identified multiple cardiac A-kinase anchoring proteins (AKAPs) that scaffold AC near upstream and downstream signaling partners to provide a means of spatial and temporal regulation of cAMP and cardiac function. But is AKAP scaffolding required for all cAMP effectors? We hypothesize that 1) AKAP-independent anchoring of AC to effector complexes is a major contributor to cAMP sensitivity and 2) both AKAP-dependent and AKAP-independent macromolecular AC-effector complexes are required for cardiac function. In support of this hypothesis, we have identified a new AC scaffolding protein, the Popeye Domain-Containing protein, Popdc. Popdc isoforms are transmembrane proteins that are important for pacemaker function, reperfusion injury, and muscle regeneration. Importantly, Popdc represents a novel cAMP effector, with a cytosolic cAMP binding domain that regulates protein-protein interactions. Clinically, mutation of human Popdc1 (S201F) reduces cAMP binding by 50% and causes Limb-Girdle Muscular Dystrophy and Cardiac Arrhythmia. In sinoatrial node, cAMP-dependent Popdc regulation of the potassium channel TREK-1 acts to control heart rate. Our recent studies of AC9-/- mice show that AC9 is also an important regulator of basal cardiac function and heart rate, while preliminary data show a complex of AC9-Popdc-TREK. Additionally, Popdc regulates AC9 activity in a cAMP-dependent manner. Thus, the Popdc proteins have all the scaffolding, feedback, and effector regulatory properties that AKAP-PKA complexes create, but bundled in one unique protein.
Three specific aims are proposed to examine the role of this novel AC complex on cardiac function.
Aim 1, Identify specificity and interaction sites for AC-Popdc complexes.
Aim 2, Determine the mechanism of Popdc regulation of AC activity.
Aim 3, Examine functional roles for AC-Popdc complexes in heart. Our studies have important implications not only for cardiac muscle, but for skeletal muscle regulation and possibly additional AC isoforms.

Public Health Relevance

Abnormal heart rhythms or arrhythmias can trigger fainting, seizures, or even sudden death. The Center for Disease Control estimates that 2.7-6.1 million individuals in the US suffer from arrhythmias. We have identified a novel complex of three proteins that upon deletion of any member causes alterations in heart rate and/or arrhythmias in mice. Importantly, mutation of one component of the complex causes Limb-Girdle Muscular Dystrophy and Cardiac Arrhythmia in patients. Preliminary data suggest a model where this complex responds to sympathetic signals to locally regulate pacemaker activity. Our studies will provide a better understanding of mechanisms that give rise to alterations in heart rate and irregular heart rhythms and uncover new strategies for therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060419-19
Application #
9608748
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2000-07-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Navarro, Gemma; Cordomí, Arnau; Casadó-Anguera, Verónica et al. (2018) Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase. Nat Commun 9:1242
Ferré, Sergi; Bonaventura, Jordi; Zhu, Wendy et al. (2018) Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase. Front Pharmacol 9:243
Baldwin, Tanya A; Dessauer, Carmen W (2018) Function of Adenylyl Cyclase in Heart: the AKAP Connection. J Cardiovasc Dev Dis 5:
Dessauer, Carmen W; Watts, Val J; Ostrom, Rennolds S et al. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol Rev 69:93-139
Li, Yong; Baldwin, Tanya A; Wang, Yan et al. (2017) Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction. Sci Rep 7:5522
Dessauer, Carmen W (2017) Shining a light on GPCR complexes. J Biol Chem 292:14290-14291
Brust, Tarsis F; Alongkronrusmee, Doungkamol; Soto-Velasquez, Monica et al. (2017) Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties. Sci Signal 10:
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
Brand, Cameron S; Sadana, Rachna; Malik, Sundeep et al. (2015) Adenylyl Cyclase 5 Regulation by G?? Involves Isoform-Specific Use of Multiple Interaction Sites. Mol Pharmacol 88:758-67
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 G? and G??. PLoS Comput Biol 11:e1004598

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