Modulation of Synaptic AMPA-Glutamate Receptors by Polysialic Acid: A Potential Therapeutic Strategy for Ameliorating Neurological Disorders
Disciplines
Molecular and Cellular Neuroscience
Abstract (300 words maximum)
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) subtype of glutamate receptors is a crucial mediator of fast excitatory neurotransmission within the mammalian central nervous system. Precise regulation of AMPA receptors is essential for normal synaptic transmission. Numerous endogenous molecules play pivotal roles in modulating the functional characteristics of AMPA receptors. One such molecule is polysialic acid (PSA), a highly negatively charged carbohydrate covalently attached to the neural cell adhesion molecule (NCAM), which is prominently expressed in hippocampal synapses. Although previous research has demonstrated that PSA-NCAM can influence the single-channel properties of purified and reconstituted AMPA receptors, its impact on native synaptic AMPA receptors has remained unexplored.
In this study, we employed the isolation and functional reconstitution of synaptosomal AMPA receptors in lipid bilayers to investigate the effects of PSA on synaptic AMPA receptors. Our findings revealed that PSA, in a concentration-dependent manner, exerts several noteworthy effects on AMPA receptors. It enhances the single-channel open probability, prolongs the mean open time, and reduces the mean closed time of these receptors. Notably, the well-known AMPA receptor desensitization blocker, Cyclothiazide, was unable to block the effects of PSA. This implies that PSA can modulate AMPA receptor channel properties independently of desensitization blockade, a phenomenon observed in certain pathological conditions.
Taken together, our results indicate that PSA enhances the single-channel activity of synaptic AMPA receptors. Beyond reducing the rate of desensitization, PSA appears to potentiate AMPA receptors through alternative mechanisms. A comprehensive understanding of the dynamics of the interaction between PSA and AMPA receptors holds the potential to expand the utility of PSA as a small molecule therapeutic compound in various disease states characterized by AMPA receptor dysfunction.
Academic department under which the project should be listed
CSM - Molecular and Cellular Biology
Primary Investigator (PI) Name
Vishnu Suppiramaniam
Additional Faculty
Catrina Sims-Robinson, Department of Neurology, College of Medicine, Medical University of South Carolina, robinsoc@musc.edu
Kawsar Chowdhury, Department of Molecular and Cellular Biology, Kennesaw State University, kchowdhu@kennesaw.edu
Modulation of Synaptic AMPA-Glutamate Receptors by Polysialic Acid: A Potential Therapeutic Strategy for Ameliorating Neurological Disorders
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) subtype of glutamate receptors is a crucial mediator of fast excitatory neurotransmission within the mammalian central nervous system. Precise regulation of AMPA receptors is essential for normal synaptic transmission. Numerous endogenous molecules play pivotal roles in modulating the functional characteristics of AMPA receptors. One such molecule is polysialic acid (PSA), a highly negatively charged carbohydrate covalently attached to the neural cell adhesion molecule (NCAM), which is prominently expressed in hippocampal synapses. Although previous research has demonstrated that PSA-NCAM can influence the single-channel properties of purified and reconstituted AMPA receptors, its impact on native synaptic AMPA receptors has remained unexplored.
In this study, we employed the isolation and functional reconstitution of synaptosomal AMPA receptors in lipid bilayers to investigate the effects of PSA on synaptic AMPA receptors. Our findings revealed that PSA, in a concentration-dependent manner, exerts several noteworthy effects on AMPA receptors. It enhances the single-channel open probability, prolongs the mean open time, and reduces the mean closed time of these receptors. Notably, the well-known AMPA receptor desensitization blocker, Cyclothiazide, was unable to block the effects of PSA. This implies that PSA can modulate AMPA receptor channel properties independently of desensitization blockade, a phenomenon observed in certain pathological conditions.
Taken together, our results indicate that PSA enhances the single-channel activity of synaptic AMPA receptors. Beyond reducing the rate of desensitization, PSA appears to potentiate AMPA receptors through alternative mechanisms. A comprehensive understanding of the dynamics of the interaction between PSA and AMPA receptors holds the potential to expand the utility of PSA as a small molecule therapeutic compound in various disease states characterized by AMPA receptor dysfunction.