Genomes and Genes
Control of Junctional Conductance at Auditory Afferent
Principal Investigator: Alberto Pereda
Abstract: Abstract The long-term objective of the proposed research is to study the role and properties of electrical synaptic transmission via gap junctions in the CNS, in particular in the auditory system. The goldfish Mauthner (M-) cell system is ideally suited for these studies since unlike mammalian electrical synapses, the experimental accessibility makes it possible to quantify in vivo changes in junctional conductance that occur under different physiological conditions and to correlate them with anatomical, ultrastructural and molecular analysis. Our progress shows that the conductance of these electrical synapses is under the fine regulatory control of glutamatergic synapses co-localized in the same terminals. Further, our progress also shows that electrical transmission is mediated by Connexin 35 (Cx35), the fish ortholog of the mammalian Connexin 36, suggesting that mammalian electrical synapses could be similarly modulated. This proposal focuses now on understanding the molecular mechanisms underlying changes in junctional conductance. We will investigate if, in analogy to the role of scaffold proteins in chemical synapses, mechanisms of exo/endocytosis involving interactions with the scaffold ZO-1 are necessary for activity-dependent potentiation of junctional conductance. Aim 1, is to investigate the association and interaction of Cx35 with the scaffold protein ZO-1. The scaffold protein ZO-1 is known to interact with many connexins to regulate their surface expression. Our preliminary results indicate that this protein co-localizes and directly interacts with Cx35 through conserved regions of both Cx35 and Cx36 carboxy-terminus. We propose to characterize direct protein-protein interactions between Cx35 and ZO-1. Aim 2, investigates the role of the Cx35/ZO-1 association in regulating electrical synaptic transmission. It is based on evidence suggesting the existence of active trafficking of gap junction channels and that potentiation could be prevented by intracellular injections of both botulinum toxin (that block exocytosis) and by peptides that interfere with Cx35/ZO-1 interactions. The proposed research addresses the novel concept that the strength of electrical synapses is dynamically modified by the activity of nearby chemical synapses. ZO-1 could become as a result of the proposed investigations the first regulatory protein identified for electrical transmission. Furthermore, its direct interaction through conserved regions of both Cx35 and Cx36 carboxy-terminus suggests that its function might underlie a fundamental and widespread property of electrical transmission, also relevant to mammalian electrical synapses. This property could be widespread and relevant to pathological conditions such as epilepsy and developmental disorders.
Funding Period: 1997-01-01 - 2010-06-30
more information: NIH RePORT
- Functional specializations of primary auditory afferents on the Mauthner cells: interactions between membrane and synaptic propertiesSebastian Curti
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
J Physiol Paris 104:203-14. 2010..The striking functional specializations of these neurons suggest that primary auditory afferents might be capable of more sophisticated contributions to auditory processing than has been generally recognized...
- Gap junction-mediated electrical transmission: regulatory mechanisms and plasticityAlberto E Pereda
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
Biochim Biophys Acta 1828:134-46. 2013..Like their chemical counterparts, electrical synapses can also be plastic and modifiable. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions...
- Molecular and functional asymmetry at a vertebrate electrical synapseJohn E Rash
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
Neuron 79:957-69. 2013....
- Variability of distribution of Ca(2+)/calmodulin-dependent kinase II at mixed synapses on the mauthner cell: colocalization and association with connexin 35Carmen E Flores
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
J Neurosci 30:9488-99. 2010..Together, our results indicate that CaMKII should be considered a component of electrical synapses, although its association is nonobligatory and likely driven by activity...
- Trafficking of gap junction channels at a vertebrate electrical synapse in vivoCarmen E Flores
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Proc Natl Acad Sci U S A 109:E573-82. 2012....