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Abstract
Each day, approximately 0.5-0.9 l of water diffuses through (primarily) aquaporin-1
(AQP1) channels in the human choroid plexus, into the cerebrospinal fluid of the brain
ventricles and spinal cord central canal, through the ependymal cell lining, and into
the parenchyma of the CNS. Additional water is also derived from metabolism of glucose
within the CNS parenchyma. To maintain osmotic homeostasis, an equivalent amount of
water exits the CNS parenchyma by diffusion into interstitial capillaries and into
the subarachnoid space that surrounds the brain and spinal cord. Most of that efflux
is through AQP4 water channels concentrated in astrocyte endfeet that surround capillaries
and form the glia limitans. This report extends the ultrastructural and immunocytochemical
characterizations of the crystalline aggregates of intramembrane proteins that comprise
the AQP4 "square arrays" of astrocyte and ependymocyte plasma membranes. We elaborate
on recent demonstrations in Chinese hamster ovary cells of the effects on AQP4 array
assembly resulting from separate vs. combined expression of M1 and M23 AQP4, which
are two alternatively spliced variants of the AQP4 gene. Using improved shadowing
methods, we demonstrate sub-molecular cross-bridges that link the constituent intramembrane
particles (IMPs) into regular square lattices of AQP4 arrays. We show that the AQP4
core particle is 4.5 nm in diameter, which appears to be too small to accommodate
four monomeric proteins in a tetrameric IMP. Several structural models are considered
that incorporate freeze-fracture data for submolecular "cross-bridges" linking IMPs
into the classical square lattices that characterize, in particular, naturally occurring
AQP4.