This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gap junction communication is critical for fundamental biological processes in the heart including growth and development, impulse propagation and responses to physiological and pathological stimuli. Of the 2 cardiac connexins expressed in working ventricular myocytes, far less is known about the distribution and function of Cx45 than the principal ventricular gap junction channel protein, Cx43. The long-term goal of our laboratory is to define the role of Cx45 in normal and diseased hearts.
The Specific Aims of this application are focused on 4 aspects of Cx45 function in the normal heart: 1) interaction with Cx43 at intercellular junctions;2) biophysical characterization of Cx45/Cx43 hybrid gap junction channels;3) mechanisms regulating changes in Cx45 expression in response to physiological stimuli;and 4) alterations in intercellular coupling resulting from increased expression of Cx45 relative to Cx43.
In Aim 1, double-label immunoelectron microscopy will be used to determine the subcellular colocalization of Cx45 and Cx43 in cardiac gap junctions.
In Aim 2, single channel recordings via dual whole-cell voltage-clamp procedures will be used to elucidate unique properties of Cx45/Cx43 hybrid gap junction channels in native ventricular myocytes from wild-type, transgenic Cx45-overexpressing and Gx43-null mice.
In Aim 3, cardiac myocytes will be subjected to defined pulsatile stretch to induce upregulation of Cx45 expression;mechanisms responsible for this acute response to mechanical stimulation including changes in Cx45 trafficking and activation of integrin signaling pathways will be delineated.
In Aim 4, Lucifer yellow dye transfer studies in myocytes expressing different levels of Cx45 and Cx43 will reveal how increased expression of Cx45 relative to Cx43 alters intercellular coupling. These studies will provide new insights into homeostatic mechanisms controlling distribution of Cx45 and Cx43 in the normal heart, and how connexin remodeling in disease states such as myocardial ischemia, adaptive hypertrophy and end-stage heart failure disrupts normal intercellular communication.
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