Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system.
The panglial syncytium maintains ionic conditions required for normal neuronal electrical activity in the central nervous system (CNS). Vital among these homeostatic functions is "potassium siphoning," a process originally proposed to explain astrocytic sequestration and long-distance disposal of K(+) released from unmyelinated axons during each action potential. Fundamentally different, more efficient processes are required in myelinated axons, where axonal K(+) efflux occurs exclusively beneath and enclosed within the myelin sheath, precluding direct sequestration of K(+) by nearby astrocytes. Molecular mechanisms for entry of excess K(+) and obligatorily-associated osmotic water from axons into innermost myelin are not well characterized, whereas at the output end, axonally-derived K(+) and associated osmotic water are known to be expelled by Kir4.1 and aquaporin-4 channels concentrated in astrocyte endfeet that surround capillaries and that form the glia limitans. Between myelin (input end) and astrocyte endfeet (output end) is a vast network of astrocyte "intermediaries" that are strongly inter-linked, including with myelin, by abundant gap junctions that disperse excess K(+) and water throughout the panglial syncytium, thereby greatly reducing K(+)-induced osmotic swelling of myelin. Here, I review original reports that established the concept of potassium siphoning in unmyelinated CNS axons, summarize recent revolutions in our understanding of K(+) efflux during axonal saltatory conduction, then describe additional components required by myelinated axons for a newly-described process of voltage-augmented "dynamic" potassium siphoning. If any of several molecular components of the panglial syncytium are compromised, K(+) siphoning is blocked, myelin is destroyed, and axonal saltatory conduction ceases. Thus, a common thread linking several CNS demyelinating diseases is the disruption of potassium siphoning/water transport within the panglial syncytium. Continued progress in molecular identification and subcellular mapping of glial ion and water channels will lead to a better understanding of demyelinating diseases of the CNS and to development of improved treatment regimens.
Department of Biomedical Sciences, Program in Neuronal Growth and Development, and Program in Cell and Molecular Biology, Campus Delivery 1617, Colorado State University, Fort Collins, CO 80523, USA. john.rash@colostate.edu
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D000818:Animals; D001369:Axons / Q000378:metabolism*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D009457:Neuroglia / Q000378:metabolism*; D009471:Neuromyelitis Optica / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*
D011188:Potassium