Gap Junction Channels and Hemichannels as a Therapeutic Target in Stroke

Title : Gap Junction Channels and Hemichannels as a Therapeutic Target in Stroke

Abstract:

Connexin and pannexin membrane channel proteins for gap junctions which are conduits that allow neuronal, glial, and vascular tissues interactions. In the brain, this interaction is highly critical for homeostasis and brain repair after injury. The main gap junction protein in the brain, Connexin43 (Cx43), is mainly present in astrocytes; its function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of a permanent middle cerebral artery occlusion (MCAO) stroke model in mice that were wild-type (WT) or knock-in of Cx43 with serine to alanine mutations at the protein kinase-C site Cx43^S368A (PKC), the casein kinase-1 sites Cx43^{S325A/328Y/330A} (CK1) and the mitogen-activated protein kinase sites Cx43^{S255/262/279/282A} (MK4). We demonstrate that MK4 transgenic animals exhibit a significant decrease in infarct volume which was associated with significant behavioral improvement. An increase in astrocyte reactivity with a concomitant decrease in microglial reactivity was observed in MK4 mice. In contrast to WT, MK4 astrocytes displayed reduced Cx43 hemichannel activity. To further validate the potential of targeting Cx43 hemichannels in stroke, pharmacological blockade of Cx43 hemichannels with TAT-Gap19 significantly decreased infarct volume in WT animals. This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function. Understanding the molecular mechanisms by which these membrane channels function, in health and disease, might be particularly influential in establishing conceptual frameworks to develop new therapeutics against connexin and pannexin channels.

Biography:

Dr. Christian Naus received a PhD in Anatomy (1985) from Western University, followed by postdoctoral studies at the Scripps Clinic in La Jolla, CA. He started his academic career as an MRC Scholar in the Faculty of Medicine at Western University in 1987.  He was recruited to the Faculty of Medicine at the University of British Columbia in 2002 to Head the Departments of Anatomy & Cell Biology, and Physiology, and merged them into the current Department of Cellular & Physiological Sciences. He became Director of the Life Sciences Institute from 2009-2013, promoting interdisciplinary discovery research in biomedical and health sciences.  Dr. Naus was recipient of a Canada Research Chair in Gap Junctions in Neurological Disorders, and is an elected Fellow of the Canadian Academy of Health Sciences. His research program explores the role of gap junction channels and their proteins (connexins and pannexins) in disease, including consequences of mutations on gap junction structure and function, and the role of these intercellular channels in diagnosis of disease and development of novel therapeutic strategies.  He has conducted over 25 years of research in neurobiology and cancer, focused on cellular and molecular studies to characterize the role of gap junctions in proliferation, differentiation, transgenic mouse models of neurological disorders, and preclinical therapeutic studies for stroke, cancer and Alzheimer’s disease.