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Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate

1
Department of Behavioral Physiology, Graduate School of Human Sciences, Osaka University, Osaka 565-0871, Japan
2
Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Korea
3
Department of Oral Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan
4
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 563; https://doi.org/10.3390/ijms21020563 (registering DOI)
Received: 25 November 2019 / Revised: 11 January 2020 / Accepted: 14 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABAAR-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABAAR currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABAAR-mediated currents. Hump-like GABAAR currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABAAR-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABAAR-mediated currents and their functional significances. View Full-Text
Keywords: GABAA receptor; desensitization; resensitization GABAA receptor; desensitization; resensitization
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Kang, Y.; Saito, M.; Toyoda, H. Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate. Int. J. Mol. Sci. 2020, 21, 563.

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