GABA-Receptor Modulation in the Treatment of Neurological Diseases
WASHINGTON, December 4, 2018 (Newswire.com) - An article published in Experimental Biology and Medicine (Volume 243, Issue 13, September 2018)(https://journals.sagepub.com/doi/full/10.1177/1535370218800980) identifies new mechanisms that regulate the activity of the most common type of receptor in the mammalian brain, GABA receptors. The study, led by Dr. Sergiy Sylantyev in the Centre for Clinical Brain Sciences at the University of Edinburgh in Edinburgh, UK, reports that numerous intracellular signaling pathways differentially regulate the activity of GABA receptor subtypes.
Neurons transmit information in the brain and communicate with each other through surface molecules called receptors. These receptors can activate or inhibit neuronal activity. The main inhibitory receptor in the mammalian brain, GABA-A-receptors (GABAARs), are activated by the neurotransmitter GABA, which is released from neurons. Because inhibitory receptor activation is a key factor in suppressing the increased neuronal activity associated with epilepsy, increasing the GABA concentration in the brain is a classical approach to treatment of epilepsy. However, increasing GABA levels is accompanied by numerous detrimental side effects. Targeting a newly discovered GABA receptor subtype (s-GABAAR) that can but does not require GABA for activation may eliminate the need to modulate GABA levels and reduce side effects.
In the current study, Dr. Sylantyev and Mr. O’Neill examined the molecular mechanisms that regulate s-GABAAR activity in neural cells from an area of the brain that is commonly affected in epilepsy, the dentate gyrus. GABA-independent receptor activity was regulated by G-protein and other signaling pathways. In contrast, GABA-dependent receptor activity was regulated by the protein kinase C signaling pathway. Both GABA-dependent and GABA-independent receptor activity modulated outgoing signals from and integration of incoming signals to neurons. Thus, modulation of the signaling pathways that regulate s-GABARs activity may provide new and safer treatments for epilepsy. Dr. Sylantyev said that “GABA-independent modulation of spontaneously opening GABA-receptors is a perspective direction for the search for new anti-epileptic drugs free from common side effects.”
Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said, “Sylantyev and O’Neill have studied the role of PKC and G-Proteins in regulating s-GABAARs’ activation and deactivation. Their studies will impact future therapeutics for neurologic disorders including epilepsy.”
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Source: Experimental Biology and Medicine