Diseases associated with leaky hemichannels

Abstract

Hemichannels (HCs) and gap junction channels (GJCs) formed by protein subunits called connexins (Cxs) are major pathways for intercellular communication. While HCs connect the intracellular compartment with the extracellular milieu, GJCs allow the interchange of molecules between cytoplasm of two contacting cells. Under physiological conditions, HCs are mostly closed, but they can open under certain stimuli allowing the release of autocrine and paracrine molecules. Moreover, some pathological conditions, like ischemia or other inflammation conditions, significantly increase HCs activity. In addition, some mutations in Cx genes associated with human diseases, such as deafness or cataracts, lead to the formation of more active HCs or "leaky HCs." In this article we will revise cellular and molecular mechanisms underlying the appearance of leaky HCs, and the consequences of their expression in different cellular systems and animal models, in seeking a common pattern or pathological mechanism of disease.

Keywords: cell death; connexins; disease; gap junction channels; leaky hemichannels; mutations.

FIGURE 1

Topology of connexin (Cx) at the plasma membrane. Cartoon depicting the plasma membrane topology shared by all Cx isoforms, which includes four transmembrane (TM) segments that are connected by two extracellular loops (ELs) and one intracellular loop (IL). The amino terminal (NT) and carboxi terminal (CT) segments of each hemichannel face the cytoplasm. The length of the NT and CT segments is not intended to represent any particular Cx isoform.

FIGURE 2

Plasma membrane arrangements of Cxs. Six Cxs oligomerize to form a HC that traveled to the non-appositional plasma membrane to form free HCs, which provide an auto/paracrine communication pathway between the cell and the extracellular milieu. Alternatively, can dock others HCs provided by an adjacent cell (appositional plasma membrane) to form intercellular aqueous pore named gap junction channels.

FIGURE 3

Representation of the effects of leaky HC. Under normal conditions (upper panel) HCs present a low open probability (OP). Thus, when HCs are normally closed (t₀, low OP), no exchange with the extracellular milieu is observed. However, when HCs open (t₁, higher OP), molecules such as ATP and Ca²⁺ can flow through them. Calcium may activate intracellular pathways, and ATP released from the cell, can act as a paracrine -or autocrine- signal, hence, the cell is at a communicating state. In contrast leaky HCs (lower panel) maintain a high OP, producing a continuous flow out and into the cell. Leaky HCs exchange continuously, resulting in the reduction of cell membrane potential and later cell death (t₂).