Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Xiong, Wei; Chen, Shao Rui; He, Long; Cheng, Kejun; Zhao, Yi; Chen, Hong; Li, De Pei; Homanics, Gregg E.; Peever, John H.; Rice, Kenner C.; Wu, Ling Gang; Pan, Hui Lin; Zhang, Li

doi:10.1038/nn.3615

Cited by 57 publications

(69 citation statements)

References 49 publications

(91 reference statements)

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“…Of interest was the observation that dehydroxyl-CBD (1μM) was more efficacious than CBD as it initiated a 9-fold increase in current amplitude. This observation led to the more recent study highlighting a role for dehydroxyl-CBD in modulating presynaptic GlyR and suggested a homomeric conformational bias for dehydroxyl-CBD effects [40].…”

Section: Glycine Receptorsmentioning

confidence: 97%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Glycine Receptorsmentioning

confidence: 97%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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“…For example, GlyRs are broadly expressed in brain (Lynch, 2009;Dutertre et al, 2012;Salling and Harrison, 2014) and are located extrasynaptically (Muller et al, 2008;Xu and Gong, 2010), presynaptically (Jeong et al, 2003;Xiong et al, 2014), and postsynaptically (Dumoulin et al, 2001), depending on the brain region and cell type studied. GlyRs from humans and rats contain three subtypes of a subunits (a1-3) and one b subunit (Grenningloh et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the a4 subunit is found in mice (Matzenbach et al, 1994) and chicks (Harvey et al, 2000). GlyRs in adult animals consist of heteromeric ab and homomeric a subunits (Lynch, 2009;Xiong et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

J Pharmacol Exp Ther

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Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyRa1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyRa2 and a3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyRa2 or a3 subunits were distinct from effects previously observed in mice with knock-in mutations in the a1 subunit. We provide evidence that GlyRa2 and a3 subunits may regulate ethanol consumption and the aversive response to ethanol.

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“…20 These receptors are also expressed in the hippocampus [21][22][23][24][25] and in the cortex. 26,27 Importantly, GlyR heteromers cluster at the presynaptic membrane to control neurotransmitter release in the medial nucleus of trapezoid body in the brainstem, 28 the spinal cord 29,30 and the ventral tegmental area. 31 During neurogenesis, extrasynaptic GlyRs and their ligands are present in the forebrain 32,33 as well as in neurogenic regions of the postnatal brain.…”

mentioning

confidence: 99%

Glycine receptors control the generation of projection neurons in the developing cerebral cortex

Ávila

Tielens

et al. 2014

Cell Death Differ

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The development of the cerebral cortex requires coordinated regulation of proliferation, specification, migration and differentiation of cortical progenitors into functionally integrated neurons. The completion of the neurogenic program requires a dynamic interplay between cell intrinsic regulators and extrinsic cues, such as growth factor and neurotransmitters. We previously demonstrated a role for extrasynaptic glycine receptors (GlyRs) containing the a2 subunit in cerebral cortical neurogenesis, revealing that endogenous GlyR activation promotes interneuron migration in the developing cortical wall. The proliferative compartment of the cortex comprises apical progenitors that give birth to neurons directly or indirectly through the generation of basal progenitors, which serve as amplification step to generate the bulk of cortical neurons. The present work shows that genetic inactivation of Glra2, the gene coding the a2 subunit of GlyRs, disrupts dorsal cortical progenitor homeostasis with an impaired capability of apical progenitors to generate basal progenitors. This defect results in an overall reduction of projection neurons that settle in upper or deep layers of the cerebral cortex. Overall, the depletion of cortical neurons observed in Glra2-knockout embryos leads to moderate microcephaly in newborn Glra2-knockout mice. Taken together, our findings support a contribution of GlyR a2 to early processes in cerebral cortical neurogenesis that are required later for the proper development of cortical circuits. The cerebral cortex develops from the forebrain and contains different classes of neurons distributed within layers that are regionally organized into sensory, motor and association areas. Cerebral cortex layering arises inside-out as progenitors give birth to successive waves of pyramidal projection neurons in the dorsal telencephalon 1 and GABAergic interneurons in the ventral forebrain.2 Projection neurons migrate radially to settle in appropriate layers of the cortical plate (CP) from where they grow axonal projections towards cortical or subcortical targets. Interneurons migrate from the ganglionic eminences along multiple tangential paths to integrate local cortical networks. More generally, the development of the cortex progresses through successive steps including proliferation, specification, migration and neuronal differentiation. Disrupting the completion of one or several of these cellular events may lead to severe cortical malformations underlying neurological disorders characterized by learning and intellectual disability or epilepsy.

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Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Cited by 57 publications

References 49 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Glycine receptors control the generation of projection neurons in the developing cerebral cortex

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