Connexin Hemichannels in Astrocytes: An Assessment of Controversies Regarding Their Functional Characteristics

Abstract

Astrocytes in the mammalian central nervous system are interconnected by gap junctions made from connexins of the subtypes Cx30 and Cx43. These proteins may exist as hemichannels in the plasma membrane in the absence of a 'docked' counterpart on the neighboring cell. A variety of stimuli are reported to open the hemichannels and thereby create a permeation pathway through the plasma membrane. Cx30 and Cx43 have, in their hemichannel configuration, been proposed to act as ion channels and membrane pathways for different molecules, such as fluorescent dyes, ATP, prostaglandins, and glutamate. Published studies about astrocyte hemichannel behavior, however, have been highly variable and/or contradictory. The field of connexin hemichannel research has been complicated by great variability in the experimental preparations employed, a lack of highly specific pharmacological inhibitors and by confounding changes associated with genetically modified animal models. This review attempts to critically assess the gating, inhibition and permeability of astrocytic connexin hemichannels and proposes that connexins in their hemichannel configuration act as gated pores with isoform-specific permeant selectivity. We expect that some, or all, of the controversies discussed here will be resolved by future research and sincerely hope that this review serves to motivate such clarifying investigations.

Pannexin 1 activation and inhibition is permeant‐selective

“…; Nielsen et al . ). According to these parallel comparisons conducted in both mammalian cells and Xenopus oocytes expressing Panx1, pharmacological inhibitors do not affect Panx1‐mediated permeabilities equally.…”

“…The well‐established connexin hemichannel inhibitors lanthanum and flufenamic acid (Nielsen et al . ) had little inhibitory effect on ethidium uptake and membrane currents in Panx1‐expressing oocytes (Bruzzone et al . ; Pelegrin & Surprenant, ; Ma et al .…”

“…,b; Nielsen et al . ). It remains unresolved to what extent fluorescent dye permeability through Panx1 reflects permeation of biological molecules and atomic ions.…”

Connexin 43 hemichannels and pannexin‐1 channels contribute to the α‐synuclein‐induced dysfunction and death of astrocytes

“…At the other end, pannexins channels or pannexons result from the oligomerization of pannexins, a three‐member family of proteins that have equivalent secondary and tertiary structures than connexins with the ability to form plasma membrane channels (Iglesias, Dahl, Qiu, Spray, & Scemes, ). Although the opening of hemichannels has been proposed as a mechanism of gliotransmission linked to synaptic transmission, plasticity, and memory (Chever, Lee, & Rouach, ; Meunier et al, ; Stehberg et al, ), other studies have raised doubts about the hypothetical role of hemichannels under physiological conditions (Nielsen, Hansen, Ransom, Nielsen, & Macaulay, ). Despite the data status about this matter is still inconclusive in the connexin field, what seems most clear is the participation of hemichannels and pannexons in the homeostatic disturbances linked to the pathogenesis and progression of different diseases (Leybaert et al, ; Orellana et al, ; Salameh, Blanke, & Dhein, ).…”

Inhibition of astroglial connexin43 hemichannels with TAT‐Gap19 exerts anticonvulsant effects in rodents

“…When open, Cx43 HCs form a high conductance pathway (single channel conductance of ∼220 pS) allowing the passage of molecules and ions below ∼1.5 kDa (Wang et al, ). Some controversies regarding the functional characteristics of Cx43 HCs are described (reviewed in Nielsen, Hansen, Ransom, Nielsen, & MacAulay, ), however, several research papers demonstrate that, if opening is limited in nature, glial Cx43 HCs may provide a pathway for controlled release of various neuroactive substances, called gliotransmitters (e.g., glutamate and adenosine triphosphate (ATP) release; Orellana et al, ; Ye, Wyeth, Baltan‐Tekkok, & Ransom, ) or the entry of major signaling ions like Ca 2+ . The latter will transiently increase the intracellular Ca 2+ concentration ([Ca 2+ ] i ), which can affect a variety of physiological cell functions (e.g., regulation of cell volume and synaptic activity; Chever, Lee, & Rouach, ; Chever, Pannasch, Ezan, & Rouach, 2014; Lohman & Isakson, ; Meunier et al, ; Giaume, Leybaert, Naus, & Sáez, ; Orellana et al, ; Pannasch & Rouach, ; Torres et al, ; Walrave et al, ).…”