Chemokine receptor-4 regulation of Beta adrenergic-mediated calcium channel

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DESCRIPTION (provided by applicant): The chemokine, Stromal Cell Derived Factor-1 (SDF1) (also known as, CXCL12) and its major receptor, CXCR4, have long been thought to have a negative impact on myocardial function, however, there is growing evidence that has expanded their role beyond inflammation and orchestrating chemotaxis. Recent observations demonstrated that CXCR4 is constitutively expressed on cardiac myocytes (CM) and is negatively modulating cardiac contractile function. We have also demonstrated that SDF-1/CXCR4 activation prevents the increase in diastolic intracellular calcium levels due to sustained exposure to isoproterenol (ISO), a non-specific 2-adrenergic agonist. Calcium imbalances have been implicated as an underlying mechanism of human cardiac dysfunction. The voltage-dependent calcium channel (VDCC) plays a critical role in calcium regulation in the heart. Thus, aberrant calcium signaling arising from this channel could initiate the calcium imbalances observed in heart failure (HF). 2-adrenorceptor (2AR)-mediated signal transduction mechanism not only regulates the contractile activity of the healthy heart, but it is also considered to play a role during the development of HF. Two major classes of drugs used to treat heart disease; beta-blockers and channel blockers target the regulation of VDCC. This underscores the important role that these channels play in heart function. We have preliminary data that activation of CXCR4, by its ligand, prevents L type VDCC (L-VDCC) internalization/recycling and reduces channel activity. Additionally, we have evidence that CXCR4 activation negatively modulates Ca2+ transient and contractile function in response to the 2-adrenergic agonist. Activation of 2AR is known to lead to an increase in calcium current through Cav1 channels in cardiac cells as a result of phosphorylation by cAMP-dependent protein kinase (PKA). We have recently demonstrated that 2AR activation induces internalization of cardiac CaV1.2 channel complexes through a 2-arrestin 1 mediated pathway. We propose to study the mechanism by which CXCR4 negatively modulates 2AR-induced positive inotropic response in CM. Our data suggest two possibilities for CXCR4 modulatory function in heart: CXCR4-mediated (i) disruption of 2AR signaling, and/or (ii) alteration in agonist-induced internalization/ desensitization of VDCC thus affecting Ca2+ handling and regulating contractile function. Our hypothesis is that SDF-1/CXCR4 activation negatively modulates L-VDCC function of the healthy heart. CXCR4 activation affects 2AR signaling and in turn alters agonist-induced internalization/ trafficking of L-VDCC. The experiments proposed will identify the mechanisms underlying CXCR4 effects on 2AR-induced L-VDCC internalization/desensitization and determine the functional significance of this interaction on calcium current and myocytes inotropic response. PUBLIC HEALTH RELEVANCE: The proposed studies will identify the mechanisms underlying SDF-1 (Stromal Cell Derived Factor-1) and its major receptor, CXCR4, effects on Beta adrenergic-induced calcium channel internalization/desensitization and determine the functional significance of this interaction on calcium current and myocytes inotropic response.