What is it about?

The emergence of consciousness from anesthesia, while involving the metabolism and excretion of anesthetic agents, is not merely a by-product of these pharmacokinetic processes. The restoration of consciousness is intricately linked to the intrinsic molecular changes in the brain that occur after anesthesia. We have recently reported that the ubiquitin degradation of KCC2 in the ventral postmedial nucleus (VPM) of the thalamus drives the emergence of consciousness from anesthesia when the brain is exposed to an anesthetic and consciousness is suppressed to the minimum responsive state(MRS) (see Hu JJ, et al., Nat Neurosci, 2023, PMID: 36973513). Here we further show that valosin-containing protein (VCP), recruited by fas-associated factor 1 (FAF1), transports the Fbxlb4-medaited ubiquitination of KCC2 to proteasomes for degradation in neurons serving as a common molecular mechanism by which the brain emerges from anesthesia and regains consciousness.

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Why is it important?

We uncover a novel pathway for the KCC2 degradation that occurs under conditions of inhibition of neuronal activity and loss of consciousness by various anesthetics, i.e., VCP recruited by FAF1 transports Fblx4-mediated ubiquitinated KCC2 to proteasomes for degradation. This pathway is distinct from the two recognized pathways that mediate KCC2 degradation under conditions of neuronal excitation: the NMDAR-Ca2+-calpain and/or BDNF-TrkB activation pathways. This finding further supports and refines our recent finding that the ubiquitin degradation of KCC2 in the VPM plays an essential role in the process by which the brain to actively emerges from anesthesia and regains consciousness, challenging the previous notion that recovery from anesthesia is merely a by-product of anesthetic metabolism.

Perspectives

Brain emergence from anesthesia and restoration of full cognitive function are complex physiological processes, and many challenging and fundamental questions remain to be answered. It is important to investigate and identify the unique cellular and molecular mechanisms and deterministic neural circuits responsible for emergence from anesthesia and recovery of full cognitive function, as well as to clarify the molecular and neural circuit mechanisms that may impede recovery from anesthesia, coma, and vegetative states. The mechanisms that lead to emergence from anesthesia and recovery of cognitive function may also help us to understand some of the general principles of brain function and to shed light on consciousness and its neural basis.

Xue-Jun Song

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This page is a summary of: VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia, Proceedings of the National Academy of Sciences, December 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2414016122.
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