Regulation of P2X purinergic receptor signalling by cholesterol

Murrell-Lagnado, Ruth D (2018) Regulation of P2X purinergic receptor signalling by cholesterol. In: Levitan, Irena (ed.) Sterol regulation of ion transport mechanisms. Current topics in membranes, 80 . Elsevier. (Accepted)

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Abstract

P2X receptors are cation-selective channels that are activated by the binding of extracellular ATP. They have a high permeability to Ca2+, Na+ and K+, and are expressed widely throughout the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems. Seven mammalian subtypes of P2X receptor subunits have been identified, P2X1-7, and those that function as homotrimeric receptors (P2X1, 2, 3, 4 and 7) are targeted to lipid rafts, although they show limited resistance to solubilisation by Triton-X-100. Recent crystal structures of P2X3 and P2X4 receptors have provided considerable high-resolution information about the architecture of this family of receptors and yet the molecular details of how they are regulated by cholesterol are unknown. Currents mediated by the P2X1-4 receptors are either inhibited or relatively insensitive to cholesterol depletion but there is no clear evidence to support the direct binding of cholesterol to these receptors. In contrast, the activity of the low affinity, pro-inflammatory P2X7 receptor is potentiated by cholesterol depletion and regions within the proximal C-terminus play an important role in coupling changes in cholesterol to the gating of the pore. Based upon our understanding of the lipid signalling events that are triggered downstream of P2X7 receptor activation, a change in the levels of cholesterol may contribute to the sensitization of receptor currents and the dilation of the pore, that occurs following prolonged, high level stimulation. This chapter focuses on the regulation of P2X7 receptor signalling by cholesterol and our current understanding of the mechanisms that underlie this.

Item Type: Book Section
Keywords: P2X purinergic receptors; P2X7; Lipid rafts; Cholesterol; Crystal structures; Inflammation; Palmitoylation
Schools and Departments: School of Life Sciences > Neuroscience
Depositing User: Ruth Murrell-Lagnado
Date Deposited: 27 Jul 2017 14:02
Last Modified: 27 Jul 2017 14:20
URI: http://sro.sussex.ac.uk/id/eprint/69492

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