Both sides now: Multiple interactions of ATP with pannexin-1 hemichannels. Focus on 'a permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP'

摘要

how atp and other nucleotides are released from intact cells is a fundamental question, given the existence of multiple purinergic receptor signaling cascades operative in most vertebrate tissues (25). It is well-established that neurons and neuroendocrine cells release ATP via classical mechanisms involving Ca2+-dependent exocytotic release of nucleotides copackaged with other neurotransmitters within specialized secretory vesicles or granules. However, many, indeed most, nonexcitable cell types locally release ATP via nonlytic mechanisms that do not involve obvious or readily measured exocytosis of nucleotide-containing vesicles or granules. An alternative mechanism for nonlytic ATP release is its facilitated efflux from the cytosolic compartment through plasma membrane transport proteins. Various membrane transport proteins or functionally characterized permeability pathways have been suggested as ATP channels, including some ATP-binding cassette (ABC)-family transporters, volume-regulated anion channels, plasma membrane variants of the mitochondrial voltage-dependent anion channel (VDAC) porins, and maxianion channels (31). Additionally, a strong and growing body of data indicates that ATP release from many cell types is mediated by so-called hemichannels composed of protein subunits from the well-characterized connexin (Cx) family or the recently described pannexin (Panx) family (19, 23, 26). Hemichannels can act as low-resistance conduits for the efflux of ATP and other cytosolic metabolites (59). The ubiquitous expression of the Panx1 gene in most tissues and cell types suggests that Panx1 hemichannels may comprise one of the most widely used efflux pathways for ATP release in different paracrine and autocrine signaling responses (4, 30). Notably, extracellular ATP itself, acting via certain P2Y or P2X receptors, can elicit intracellular signals that favor the gating of hemichannels to the open state. This facilitates a pathway of what can be termed ATP-induced ATP release linked to paracrine signaling waves that allow multiple cells within a tissue to respond proactively to environmental stresses (e.g., metabolic inhibition, mechanical shear, and microbial invasion) sensed by only a few cells at the immediate locus of environmental insult or stimulation (51). This sort of paracrine signaling can play a positive role in adaptive responses, such as ischemic preconditioning, relief of mechanical stress, or killing of invading pathogens, with clear physiological benefit to the whole animal. However, a cascade of P2 receptor activation coupled to the gating of ATP-permeable hemichannels also comprises a positive feedback loop that, if unrestrained, could lead to maladaptive and malignant depletion of intracellular ATP stores, collapse of ionic gradients, and cell death. Thus considerable attention has been directed toward the identification of endogenous factors that can inhibit or restrict the gating/conductance of hemichannels. In a paper by Qui and Dahl (40a), they describe a highly novel mechanism based on a direct inhibitory action of extracellular ATP on the gating and/or activity of pannexin-1 hemichannels.