Journal club
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JOURNAL CLUB
Journal club Charles Kennedy 1 Received: 27 July 2020 / Accepted: 13 August 2020 # Springer Nature B.V. 2020
Article summary It is now clear that receptors and ion channels do not exist and function in isolation, but instead interact with other proteins in a manner that modifies their expression and activity. By combining a genome-wide open reading frame (ORF) collection with high-throughput functional screening, Salm et al. [1] have identified a specific modulator of P2X receptors, TMEM163, which was previously identified as a transmembrane Zn2+ transporter. TMEM163 does not display ATPdependent activity per se and its actions on P2X receptors are unrelated to Zn2+ transport. When co-expressed, it potentiated ATP-evoked currents mediated by P2X1, P2X3 and P2X4 receptors and, conversely, inhibited those carried by P2X7 receptors. More detailed analysis of its actions at P2X3 receptors showed that TMEM163 potentiated ATP by shifting its concentration-response curve to the left, with a five-fold decrease in the EC50 and slowing the time-course of current decay. Surprisingly, it also substantially reduced the surface expression of P2X3 receptors. Furthermore, a knock-out of TMEM163 showed that it is necessary for ATP-evoked, pain-related behaviour in vivo. Thus, TMEM163 appears to selectively modulate P2X receptor activity in a subtype-specific manner and so is potentially a novel target for development of new analgesics.
Commentary Historically, ligand-gated ion channels (LGIC) in the plasma membrane were viewed simply as “stand alone” functional units, which opened when bound by an agonist, to allow ion * Charles Kennedy [email protected] 1
Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 161 Cathedral St, Glasgow G4 0RE, Scotland
flux across the plasma membrane. It is now apparent, however, that LGIC expression and activity is in fact much more complex and that LGIC are only one component in a multi-protein complex that includes scaffolding proteins, regulatory proteins and enzymes. Known LGIC modulators include TARPs, CNIHs and PORCN (AMPA glutamate receptors), NACHO (nicotinic acetylcholine receptors) and GARLH4, neuroligin and clptm1 (GABAA receptors) (see [1], for references). As previously discussed in Purinergic Signalling (Kennedy, C., 2009, PUSI, 5: 265–267), P2X2 receptors form a complex with nine other proteins and a constitutive interaction with one of them, the neuronal Ca2+ sensor visinin-like protein 1 (VILIP1), induced a 3-fold increase in P2X2 receptor expression at the plasma membrane and a similar increase in the peak amplitude of ATP-induced currents, as well as prolonging the life-time of the P2X2 receptor in the plasma membrane (Chaumont, S. et al., 2008, Sci. Signal., 1: ra8). Subsequently, a phosphoinositide binding protein, Pirt, was shown to inhibit P2X3 receptor activity in urinary bladder sensory nerves (Gao, X-F. et al., 2015, Nat Commun., 6: 7650). Besides their important physiological roles, these modul
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