Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

W Xiong, SR Chen, L He, K Cheng, YL Zhao… - Nature …, 2014 - nature.com
W Xiong, SR Chen, L He, K Cheng, YL Zhao, H Chen, DP Li, GE Homanics, J Peever
Nature neuroscience, 2014nature.com
Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable
research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in
diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive
cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile
startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a
hereditary startle-hyperekplexia disease. The GlyRs expressed as α1 homomers either in …
Abstract
Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a hereditary startle-hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in the auditory brainstem are more vulnerable than heteromers to hyperekplexia mutation–induced impairment. Homomeric mutants are more sensitive to DH-CBD than are heteromers, suggesting presynaptic GlyRs as a primary target. Consistent with this idea, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α1 GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency.
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