Molecular Structure and Function of the Glycine Receptor Chloride Channel

Lynch, Joseph W.

doi:10.1152/physrev.00042.2003

Cited by 698 publications

(784 citation statements)

References 418 publications

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“…Pentameric glycine ionotropic receptors (GlyR) mediate neuropathic pain and inflammation through Cl -flux where, at present, 4 α subunit (α 1-4 ) isoforms and 1 isoform of the β subunit have been described [39]. Using in vitro electrophysiological assays, CBD (1-300 μM) modulated strychnine-sensitive α1 and α1β GlyR.…”

Section: Glycine Receptorsmentioning

confidence: 99%

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: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

View full text Add to dashboard Cite

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“…Multiple genes encoding the ␣ subunits have been identified (␣1-4 in the mouse and ␣1-3 in humans), whereas there is only one ␤ subunit gene. 217,218 The ␤ subunit anchors the receptor to the cytoplasmic protein gephyrin.…”

Section: Cys-loop Ligand-gated Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Note, that there is also evidence for homooligomeric receptors built exclusively from 2 subunits (see also Fig. 2) A revised stoichiometry of and subunits Native adult GlyRs contain 1 and subunits, while native neonatal GlyRs consist of 2 and subunits (Lynch 2004;Malosio et al 1991). As with other Cys-loop receptors, all subunits contribute to the assembly of the central pore (Fig.…”

Section: Postsynaptic Membrane Specializationmentioning

confidence: 99%

“…At present, vertebrate GlyR subunits are known to be encoded by Wve separate, but related genes. There are four subunits genes (GLRA1-4, encoding 1-4) and a single one encoding the protein (GLRB) (Laube et al 2002;Lynch 2004). Alternative splicing and RNA editing can generate further heterogeneity among the subunits (Lynch 2004;Meier et al 2005).…”

Section: Postsynaptic Membrane Specializationmentioning

confidence: 99%

“…There are four subunits genes (GLRA1-4, encoding 1-4) and a single one encoding the protein (GLRB) (Laube et al 2002;Lynch 2004). Alternative splicing and RNA editing can generate further heterogeneity among the subunits (Lynch 2004;Meier et al 2005). In the 1, 2 and 3 subunits, the alternative exons modify the structures of the extracellular domain or of the intracellular loop regions.…”

Section: Postsynaptic Membrane Specializationmentioning

confidence: 99%

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Molecular architecture of glycinergic synapses

Dresbach

Nawrotzki

Kremer

et al. 2008

Histochem Cell Biol

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Synapses can be considered chemical machines, which are optimized for fast and repeated exocytosis of neurotransmitters from presynaptic nerve terminals and the reliable electrical or chemical transduction of neurotransmitter binding to the appropriate receptors in the postsynaptic membrane. Therefore, synapses share a common repertoire of proteins like, e.g., the release machinery and certain cell adhesion molecules. This basic repertoire must be extended in order to generate speciWcity of neurotransmission and allow plastic changes, which are considered the basis of developmental and/or learning processes. Here, we focus on these complementary molecules located in the presynaptic terminal and postsynaptic membrane specializations of glycinergic synapses. Moreover, as speciWcity of neurotransmission in this system is established by the speciWc binding of the neurotransmitter to its receptor, we review the molecular properties of glycine receptor subunits and their assembly into functional glycine receptors with diVerent functional characteristics. The past years have revealed that the molecular machinery underlying inhibitory and especially glycinergic postsynaptic membrane specializations is more complex and dynamic than previously anticipated from morphological studies. The emerging features include structural components as well as signaling modules, which could confer the plasticity required for the proper function of distinct motor and sensory functions.

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Molecular Structure and Function of the Glycine Receptor Chloride Channel

Cited by 698 publications

References 418 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets for Antiepileptic Drug Development

Molecular architecture of glycinergic synapses

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