Paul Sorgen, PhD
Research
Gap junction channels 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, altered phosphorylation) contributes to ventricular arrhythmias. However, the failing heart also aberrantly upregulates expression of Cx45 in ventricles, where it is normally at very low levels. There is evidence that this enhances the propensity for arrhythmias, which follows from the low conductance and high voltage-sensitivity of Cx45 channels relative to Cx43. The effect of Cx45 at the ID is likely amplified by the propensity of Cx45 to form heteromeric channels with Cx43, in which it exerts a functionally dominant effect. Unfortunately, our knowledge of the mechanisms that lead to remodeling of Cx43 is incomplete, and little is known whether expression of ventricular Cx45 in cardiac diseases is an important driver of arrhythmias.
The objective of our research is to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 dysregulation in heart disease. The central hypothesis is that unique intermolecular interactions involving the divergent C-terminus of connexins affect gap junction regulation. More specifically, we hypothesize that after a myocardial infarction, differential regulation of Cx43 and Cx45 involves specific phosphorylations and protein interactions of their carboxyl terminal domain. This is based on our studies showing activation of Pyk2 and Src in the infarct epicardial border (acute ischemia) and distal zones (left ventricle hypertrophy; late-stage remodeling) after myocardial infarction, Pyk2 and Src differentially regulate Cx43 (inhibit) and Cx45 (promote) gap junction intercellular communication, and inhibition of both Pyk2 and Src is necessary to fully restore Cx43 gap junction intercellular communication. Moreover, the Pyk2 inhibitor PF4618433 has a therapeutic effect on cardiac function in myocardial infarction rats, in part, by preventing Cx43 lateralization. The significance of our work is that discovery of how interactions mediated by the carboxyl terminal domain can be modulated would open the door to strategies to ameliorate pathological effects of altered connexin regulation in the failing heart. This information is pivotal for the role of intercellular communication in normal and diseased states to be understood and utilized for therapeutic benefit in cardiac pathologies.
The following projects are ongoing in the lab to investigate this concept:
- What drives Cx43 away from gap junctions/intercalated discs in vitro and in a murine model of myocardial infarction?
- What promotes Cx45 gap junctions/intercalated discs localization and is expression of Cx45 in left ventricle hypertrophy after myocardial infarction an arrhythmogenic substrate?
Research Opportunities
- Graduate students
- Medical students
- Master students
- Undergraduate summer research