Receptor Subtypes and Their Function Critical Appraisal

Receptor Subtypes and Their Function – Critical Appraisal Largely unselective ligands of the benzodiazepine binding site, such as diazepam, are known to elicit a wide range of in vivo effects including hypnosis, sedation, anxiolysis, and muscle relaxation. Genetically modified mice were introduced in an effort to attribute individual effects to receptors that contain specific α subunit isoforms [45]. Sedative effects were proposed to be mediated specifically by ‘α1 receptors’ (Box 3 for preferred nomenclature). Attempts were made to separate sedative from anxiolytic effects, for example by reducing or eliminating action at ‘α1 receptors’ (‘α1-sparing drugs’). It has been pointed out, however, that non-sedating anxiolytics are not generally α1-sparing in functional assays using recombinant systems [46]. Other lines of research in fact correlated β isoforms with sedative-like, ataxic, or narcosis-inducing drug efficacy 47, 48. Recent technological advances now enable approaches orthogonal to transgenic animals with drug-insensitive subunits. Optogenetic manipulations have been established that allow light-mediated control of specific receptor populations, and will further help to map their physiological roles [49]. However, this novel approach to delineating the physiological role of defined receptor subtypes requires knowledge about subunit composition and arrangement of individual receptor species that is still largely lacking (Box 2). Given that a large fraction of GABAA receptors contain two different α or β isoforms in a single receptor pentamer, it would be surprising if a single subunit that is expressed in many different receptor isoforms and in different cell populations could account for a single behavioral effect of any drug. As an illustration of the complexity, we discuss here the case of cerebellar granule ML347 synthesis (CGCs). As stated above, the high-affinity binding site for benzodiazepines has been located to the αx/γ subunit interface where x=1, 2, 3, 5, but not 4 or 6. Many cells express multiple subunit isoforms. The CGCs express many subunits, among them α1, α6, βx, and γ2. It has been shown that α1α6βxγ2 receptors dominate over α6βxγ2 receptors [50]. Work in recombinant systems indicates that α1γ2β2α1β2, α6γ2β2α6β2, α1γ2β2α6β2, and α6γ2β2α1β2 receptors all differ in their functional properties and drug sensitivities. Only receptor assemblies with an α1 subunit adjacent to γ2 are responsive to benzodiazepines [15]. How does the CGC, or any other cell, assemble receptors, and which mechanisms lead to assembly of specific pentameric arrangements? Is receptor assembly dynamic? Can drug sensitivity thereby be modulated? All these questions are still open for research. Intriguingly, modulation of receptor localization and recruitment to synaptic versus extrasynaptic sites by benzodiazepines has been shown recently to occur in a bidirectional fashion. However, the mechanism of this relocation remain to be elucidated [51]. Beyond efforts to separate the established desirable effects (such as anxiolysis) from concomitant effects (such as sedation in the context of daytime anxiolysis) by subtype-specific targeting, additional potential therapeutic concepts based on subtype-selective targeting are being investigated (partly reviewed in [52]). Among them are pain states, affective disorders such as depression, and cognitive deficits in schizophrenia, developmental disorders, and neurodegenerative disorders (reviewed in [53]). In the treatment of depression, simultaneous prescription of antidepressants and benzodiazepines has involved off-label use of several benzodiazepines for some time, but the effectiveness of benzodiazepines in treatment of depression is probably limited to anxiolysis in cases where anxiety parallels depression 54, 55. Unfortunately, there remains an overall paucity of clinical studies that would permit systematic comparison of individual benzodiazepines in the different neuropsychiatric indications in which they are being heavily used off-label.