New roles for astrocytes: gap junction hemichannels have something to communicate

Abstract

Gap junctions are clusters of aqueous channels that connect the cytoplasm of adjoining cells. Each cell contributes a hemichannel, or connexon, to each cell-cell channel. The cell-cell channels are permeable to relatively large molecules, and it was thought that opening of hemichannels to the extracellular space would kill cells through loss of metabolites, collapse of ionic gradients and influx of Ca(2+). Recent findings indicate that specific non-junctional hemichannels do open under both physiological and pathological conditions, and that opening is functional or deleterious depending on the situation. Most of these studies utilized cells in tissue culture that expressed a specific gap junction protein, connexin 43. Several such examples are reviewed here, with a particular focus on astrocytes.

Figure 1

Diagrams and equivalent circuits of cell–cell channels and hemichannels. (a) In the cell–cell channel, the conductances of the two hemichannels are in series; the circuits show both gates open at the fully open or main-state conductance, g_o (left) and one gate open at g_o and the other closed to the substate conductance, g_s (right). (b) For the hemichannel, a single element represents each state: an open-state conductance (g_o) and a substate conductance (g_s). Table 1 shows that the cell–cell open-state conductance is about half that of the hemichannel open state, consistent with series arrangement in the cell–cell channel. By contrast, the substate conductance of the hemichannel is larger than predicted from the cell–cell channel (and the substate conductance of the cell–cell channel is smaller than predicted from the hemichannel, except in Ref. [44]).

Figure 2

Connexin 43 (Cx43) hemichannels mediate cyclic-ADP-ribose (cADPR) signaling by allowing outward passage of NAD⁺. Cells, including astrocytes, express CD38, an ectoenzyme that cyclizes NAD⁺ to form cADPR. cADPR then has to cross the surface membrane to reach ryanodine receptors on the endoplasmic reticulum (ER) to trigger release of Ca²⁺ into the cytoplasm; this action can be autocrine or paracrine. A pathway using intracellular vesicles can largely restrict action to the single cell.

Figure 3

Two models for conduction of Ca²⁺ waves. (a) Ca²⁺ waves are mediated by diffusion of cytoplasmic inositol (1,4,5)-trisphosphate (IP₃) through gap junctions between cells. Evidence for this mechanism includes: (i) the waves are dependent on gap junctions, and Ca²⁺ increases in a downstream cell begin at junctions; (ii) the waves are not blocked by extracellular apyrase, an ATPase; (iii) the waves are not blocked by purine-receptor antagonists such as suramin; and (iv) the waves do not jump a gap between cells. The red lightning bolt represents a photo-uncaging stimulus (hν). (b) Ca²⁺ waves are mediated by ATP released through hemichannels. Evidence for this mechanism includes: (i) the waves require connexin expression; (ii) gap junction and hemichannel blockers prevent the waves; (iii) ATP is released by the initiator cell, and the Ca²⁺ wave extends as far as the ATP diffuses; (iv) the waves are blocked by extracellular apyrase; (v) the waves are blocked by suramin; and (vi) the waves jump cell-free gaps and are deflected by flow of medium. The red lightning bolt represents an electrical stimulus (E) that causes release of ATP by unclear and perhaps nonspecific mechanisms.