ROLE OF CONNEXIN43 IN REGULATION IN CARDIAC FUNCTION

Upstate Medical University, Syracuse NY

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Abstract

Our long-term goals are: a) to characterize the molecular mechanisms of cardiac gap junction regulation and[unreadable] b) to identify the consequences of the regulation on the function of the heart. Our previous studies have[unreadable] centered on the structural bases for the regulation of Connexin43 (Cx43), the most abundant cardiac gap[unreadable] junction protein. Using exogenous expression systems, we have shown that the carboxyl terminal region of[unreadable] Cx43 (Cx43CT) acts as a regulatory domain. Here, we propose that: a) the integrity of the Cx43CT domain[unreadable] is essential for the regulation of native cardiac gap junctions and b) this regulation plays a key role in specific[unreadable] morphological and electrophysiological changes that follow the ischemic event.[unreadable] Studies on cardiac gap junction regulation have been hindered by the lack of an appropriate experimental[unreadable] model where the function of the Cx43CT domain can be directly and specifically altered. Recently, the[unreadable] Willecke laboratory developed a "knock-out/knock-in" mouse line where the gene coding for the wild-type[unreadable] Cx43 was replaced with a truncated form that lacks most of the CT domain. These mice present us with the[unreadable] first biological system to document directly the role of Cx43CT domain on: 1) The biophysical properties and[unreadable] pH gating of cardiac gap junctions. 2) The internalization of Cx43 in response to low intracellular pH (pHi) or[unreadable] global ischemia. 3) The electrophysiological behavior of adult murine ventricle in response to low pHi and[unreadable] ischemia.[unreadable] Overall, these studies will offer data fundamental to our understanding of the molecular mechanisms of[unreadable] regulation of cardiac gap junctions and their role in heart function in health and disease.