Connexins are integral membrane proteins that oligomerize to form gap junction channels. Gap junctions composed of Cx43 mediate electrical coupling and impulse propagation in the normal working myocardium. In the failing heart, Cx43 remodeling (decreased expression, loss at intercalated discs, increased presence at lateral membranes) contributes to ventricular arrhythmias. However, the failing heart also aberrantly upregulates expression of Cx45 in ventricles, where it is normally at very low levels. This greatly enhances the propensity for arrhythmias, logically due to the low conductance and high voltage-sensitivity of Cx45 channels relative to Cx43. Crucially, the deleterious effect of Cx45 at the intercalated discs is likely amplified by the propensity of Cx45 to form heteromeric channels with Cx43, in which it has a dominant effect on the function of the resulting channels. Unfortunately, little is known about the mechanisms that drive Cx45 presence at intercalated discs or about the determinants of the functional properties of Cx45 that make its presence at ventricular intercalated discs dangerous. Studies proposed in Specific Aims 1 and 2 address novel mechanisms by which phosphorylation of the Cx45 carboxyl terminal (Cx45CT) domain modulates Cx45 protein partner interactions to increase or decrease gap junction intercellular communication in vitro and in vivo (and the differences from effects on Cx43). Specific Aim 3 focuses on determining how a recently discovered high-affinity protein-protein interaction of the Cx45CT, dimerization, affects the channel functional properties. The significance of this proposal is that discovery of how phosphorylations and interactions of the CT domain can be modulated would enable strategies to ameliorate pathological alterations of connexins the failing heart and elsewhere.
|Effective start/end date||9/10/19 → 6/30/22|
- National Institute of General Medical Sciences: $424,639.00
- Cardiology and Cardiovascular Medicine
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