Pannexins, a family of gap junction proteins expressed in brain

Abstract

Database search has led to the identification of a family of proteins, the pannexins, which share some structural features with the gap junction forming proteins of invertebrates and vertebrates. The function of these proteins has remained unclear so far. To test the possibility that pannexins underlie electrical communication in the brain, we have investigated their tissue distribution and functional properties. Here, we show that two of these genes, pannexin 1 (Px1) and Px2, are abundantly expressed in the CNS. In many neuronal cell populations, including hippocampus, olfactory bulb, cortex and cerebellum, there is coexpression of both pannexins, whereas in other brain regions, e.g., white matter, only Px1-positive cells were found. On expression in Xenopus oocytes, Px1, but not Px2 forms functional hemichannels. Coinjection of both pannexin RNAs results in hemichannels with functional properties that are different from those formed by Px1 only. In paired oocytes, Px1, alone and in combination with Px2, induces the formation of intercellular channels. The functional characteristics of homomeric Px1 versus heteromeric Px1͞Px2 channels and the different expression patterns of Px1 and Px2 in the brain indicate that pannexins form cell type-specific gap junctions with distinct properties that may subserve different functions.

Immunocytochemical study of gap junction-related protein, innexin 2, in Periplaneta americana (Blattodea: Blattidae)

“…Pannexins are thought to be tetra membrane-spinning proteins and are known to form functional channels from expression studies in Xenopus oocytes (Bruzzone et al, 2003), but whether pannexins form functional channels in vertebrate animals or are vestige proteins replaced by connexins is still unknown. Further phylogenetical studies are necessary to clarify the relationship and functional diversity of innexin, connexin and pannexin in animals.…”

ATP release from non-excitable cells

“…Pannexins are structurally homologous to connexins and can form plasma membrane channels in Xenopus oocytes [93][94][95]. Several properties and findings make pannexin 1 a very attractive candidate for an ATP-releasing channel: (1) It can be activated by membrane depolarisation in the physiological range and allows permeation of small molecules including ATP [93][94][95]; (2) it can be activated at normal extracellular Ca 2+ concentrations [93]; (3) it is activated by mechanical perturbation [95]; (4) it may open under conditions of cellular energy depletion [96]; and (5) it can be activated by increase of intracellular Ca 2+ [95,97]. In addition, important evidence suggests that the longsought P2X 7 -related pore structure may be pannexin 1 [98,99].…”

Alanine substitution scanning of pannexin1 reveals amino acid residues mediating ATP sensitivity

“…At the resting membrane potential, Panx1 channels are closed but can be activated by various mechanisms including voltage steps to positive potentials or by increasing the extracellular potassium ion concentration [2,10,19]. We have observed previously that Panx1 mediated currents as well as uptake of extracellular tracer molecules and ATP release from cells can be inhibited by ATP and other ligands of the P2X7 receptor, irrespective of whether the ligands are acting as agonist or antagonist at the receptor [18].…”

“…The most common ATP binding motif, the Walker loop [19], is absent from Panx1 protein, which has four transmembrane segments, two extracellular loops and cytoplasmic localization of the amino-and carboxy-terminal segments. Our previous mutagenesis data suggest that ATP works on Panx1 through ligand binding and R75 plays an important role in the binding because the inhibitory effect of ATP is largely decreased when R75 on the first extracellular loop of Panx1is mutated to alanine.…”