Adenylyl cyclase is the central component within the beta-adrenergic receptor signalling system and is critical for the generation of cAMP and consequently for increasing cardiac contractility in response to adrenergic stimulation. During the current program project period, major advances have been made in isolating a group of adenylyl cyclase isoforms, which are predominantly expressed in the heart. The biochemical properties of these isoforms are consistent with that of cardiac tissue adenylyl cyclases. Potent regulation by phosphorylation as well as changes in the activity and mRNA levels in heart failure has been demonstrated. In this application, we aim to expand on our previous observations as well as to elucidate new mechanisms for regulating adenylyl cyclase in both normal and pathophysiological conditions. Accordingly, we propose the following studies in this application: 1) We will examine the importance of the content and stoichiometry of type V adenylyl cyclase in the heart using transgenic models. 2) We will examine whether the desensitization of beta-adrenoceptor signaling occurs at the level of adenylyl cyclase. 3) We will examine crosstalk between cAMP signaling and various protein kinase signalling pathways. 4) We will examine the subcellular localization of adenylyl cyclase in the heart. The availability of the other projects and cores within the context of this program project, in particular, the cores for producing the transgenic models and the assessment of cardiac mechanical function of other aspects of beta-adrenergic signalling, enhances considerably the scope of this individual project.
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