Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Abstract

Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11) or the β (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABAA receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.

AMINOACID RESIDUES INVOLVED IN POSITIVE MODULATION OF a1 GLYCINE RECEPTORS BY GINKGOLIC ACID

“…Характерним її симптомом є довготривале неконтрольоване скорочення м'язів тіла у відповідь на неочікуваний тактильний чи акустичний стимули, що може супроводжуватися мимовільним падінням [9]. Причиною появи симптомів гіперплек-сії є нездатність мутантних гліцинових рецеп торів забезпечувати ефективну швид-ку гальмівну нейропередачу в централь-ній нервовій системі [10].…”

Glycine receptor mouse mutants: model systems for human hyperekplexia

“…Moreover, anaesthetic concentrations of propofol, an aromatic alcohol, as well as volatile hydrocarbons, such as halothane, enflurane, isoflurane, methoxyflurane and sevoflurane, enhance the effects of low glycine concentrations (Machado et al, 2011;Lee et al, 2013). Molecular models suggest that residues of M2 and M3 surround a water-filled pocket, in which alcohol binding could preferentially stabilize the open state (Cheng et al, 2008;Schaefer et al, 2012). Recently, the X-ray structure of a GLIC mutant was solved in the presence and absence of ethanol and other modulators representing the structural basis for ethanol potentiation of CL receptors (Sauguet et al, 2013).…”

Glycine receptors in nervous tissue and their functional role

“…Глицин (Gly) выполняет в организме целый ряд жизненно важных функций [1][2][3][4][5][6][7][8][9]. Он входит в состав многих белков и биологически активных соединений, из него синтезируются порфириновые кольца гема и пуриновые основания [10].…”

“…Данная аминокислота незаменима в регуляции нейромедиаторной синаптической трансмиссии в центральной и периферической нервной системе [1,7]. Рецепторы к Gly, локализованные во многих участках головного и спинного мозга, оказывают тормозное воздействие на нейроны, уменьшая выделение возбуждающих аминокислот [1][2][3]. В то же время глицин выступает в роли коагониста рецептора g-аминобутирата (GABA-R) и глутаматного рецептора NMDA-R [4][5][6][7][8].…”