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Review
, 370 (1672)

ATP Release Through Pannexon Channels

Affiliations
Review

ATP Release Through Pannexon Channels

Gerhard Dahl. Philos Trans R Soc Lond B Biol Sci.

Abstract

Extracellular adenosine triphosphate (ATP) serves as a signal for diverse physiological functions, including spread of calcium waves between astrocytes, control of vascular oxygen supply and control of ciliary beat in the airways. ATP can be released from cells by various mechanisms. This review focuses on channel-mediated ATP release and its main enabler, Pannexin1 (Panx1). Six subunits of Panx1 form a plasma membrane channel termed 'pannexon'. Depending on the mode of stimulation, the pannexon has large conductance (500 pS) and unselective permeability to molecules less than 1.5 kD or is a small (50 pS), chloride-selective channel. Most physiological and pathological stimuli induce the large channel conformation, whereas the small conformation so far has only been observed with exclusive voltage activation of the channel. The interaction between pannexons and ATP is intimate. The pannexon is not only the conduit for ATP, permitting ATP efflux from cells down its concentration gradient, but the pannexon is also modulated by ATP. The channel can be activated by ATP through both ionotropic P2X as well as metabotropic P2Y purinergic receptors. In the absence of a control mechanism, this positive feedback loop would lead to cell death owing to the linkage of purinergic receptors with apoptotic processes. A control mechanism preventing excessive activation of the purinergic receptors is provided by ATP binding (with low affinity) to the Panx1 protein and gating the channel shut.

Keywords: ATP; Pannexin; allosteric; conductance; permeability; potassium.

Figures

Figure 1.
Figure 1.
Single-channel currents through Panx1 channels with K+ or Na+ in the extracellular solution. (a) A pannexon in an inside–out membrane patch exposed to high extracellular [K+] and clamped at –100 mV exhibited a maximal conductance of approximately 500 pS. The fully open and fully closed states are indicated by red lines; the dashed lines indicate levels of three major subconductances. Both the bath and pipette solutions contained 140 mM KGlu, 10 mM KCl and 5 mM N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES; pH 7.5). (b) An outside–out patch exposed to a low extracellular [K+] (Ringer solution) and clamped at +50 mV containing two channels that opened to the current levels O1 and O2. Both the pipette and bath solutions contained 140 mM NaCl, 10 mM KCl and 5 mM TES (pH 7.5). As shown previously, the conversion between small and large channel conductance can be observed in the same channel in an outside–out patch by switching between normal Ringer and high K+ in the extracellular solutions [58]. (Online version in colour.)
Figure 2.
Figure 2.
Permeability and conductances of pannexons vary with the activation mode. The pannexon has high conductance and is permeable to ATP, when activated by various physiological stimuli or by elevated extracellular [K+]. Activation of pannexons only by stepping the membrane potential to positive values results in a small channel conductance and selective permeability to Cl. It is unclear which channel figuration is assumed by the caspase 3 cleaved pannexon. No direct measurements of ATP permeability of the caspase-cleaved pannexon are available, and the single-channel conductance has been reported to be 20 or 75 pS. (Online version in colour.)
Figure 3.
Figure 3.
Cartoon of pannexon activation by different stimuli. In the unstimulated pannexon (centre), the channel pore is occluded and the terminal cysteine is not accessible to thiol reagents. Activation by stepping the membrane potential to positive values renders the terminal cysteine reactive to extracellularly applied thiol reagents. The single-channel conductance under this condition is circa 50 pS (left). Activation of pannexons by elevated extracellular [K+] at any membrane potential yields a channel with high conductance (500 pS; right). In this state, the terminal cysteine (yellow dot) is not sensitive to thiol reagents, while an engineered cysteine at the extracellular vestibulum is. In high extracellular [K+], the pannexon is permeable to ATP and likely has the same configuration as pannexons activated by various physiological stimuli. (Online version in colour.)

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