A new angle on blood–CNS interfaces: A role for connexins?

Abstract

a b s t r a c tNeuronal signaling in the CNS depends on the microenvironment around synapses and axons. To prevent fluctuations in blood composition affecting the interstitial fluid and CSF, two barriers, the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are interposed between the blood and the brain/CSF compartment. Brain capillary endothelial cells (ECs) constitute the BBB whereas choroid plexus epithelial (CPE) cells form the BCSFB. The anatomical basis of these barriers is located at the level of an intercellular junctional complex that impedes paracellular diffusion. Tight and adherens junctions are known as the principal constituents of this junctional complex. Transmembrane connexins (Cxs) are the prime building blocks of plasma membrane hemichannels that combine to form intercellular gap junctions (GJ). Although Cxs co-exist within the junctional complex, their influence on tight/adherens junctions and their role in barrier function of BBB ECs and CPE has been mostly ignored. Here, we review current knowledge on the role of Cxs in the BBB, BCSFB and other interfaces that subside within the CNS. We conclude that Cxs are a rather unexplored but promising target for influencing CNS barrier function.

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

“…In support of this notion, Px1 is localized on the plasma membrane of mouse inner retinal endothelial cells (Shestopalov and Panchin, 2008). Several lines of evidence confirm the belief that the gap junction formed by Cx hexamers is a determinant of the tightness of tight junctions and is associated with oscillations of intracellular Ca 21 concentration (De Bock et al, 2014). Thus, connexins influence paracellular permeability (De Bock et al, 2011, and therefore, interfering with endothelial connexins may be a novel approach to limit BBB permeability increase.…”

‘Stealth’ nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics

“…This necessitates use of high particle concentrations (with risks of associated toxicity) to achieve therapeutic benefit [6]. Second, neural tissue is partitioned from the bloodstream by the blood-brain barrier (BBB), which has its cellular basis in tight junctions between brain capillary endothelial cells, sealing off the paracellular pathway for biomolecule transport [7]. Transcellular transport across the BBB is also tightly regulated, utilizing a limited number of carrier proteins/receptors to transport essential biomolecules (e.g.…”

Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders

“…The central nervous system (CNS) is an immunologically privileged site that is maintained by three different brain barriers: the blood-brain barrier (BBB), the BCSFB (see Glossary), and the arachnoid barrier [1]. Barriers comprising fenestrated endothelium and tightly regulated epithelium, such as the BCSFB, are believed to serve as active and selective immune-skewing gates in the steady state, whereas endothelial barriers, such as the BBB, are considered as absolute immunological barriers that block leukocyte entry into the parenchyma [2].…”