Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1798, Issue 5, Pages 947-957Publisher
ELSEVIER
DOI: 10.1016/j.bbamem.2010.01.023
Keywords
P2 purinergic receptor; P2X7 receptor; pH dependence; Patch clamp
Categories
Funding
- Deutsche Forschungsgemeinschaft [Ma1581/12-1, Schm536/6-3]
- Medical Faculty of the Martin-Luther-University Roux Program [5/09, 10/01, 13/07]
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Human P2X7 receptors (hP2X7R5) belong to the P2X family, which opens an intrinsic cation channel when challenged by extracellular ATP. hP2X7Rs are expressed in cells of the inflammatory and immune system. During inflammation, ATP and protons are secreted into the interstitial fluid. Therefore, we investigated the effect of protons on the activation of hP2X7R5. hP2X7Rs were expressed in Xenopus laevis oocytes and activated by the agonists ATP or benzoyl-benzoyl-ATP (BzATP) at different pH values. The protons reduced the hP2X7R-dependent cation current amplitude and slowed the current deactivation depending on the type and concentration of the agonist used. These effects can be explained by (i) the protonation of ATP, which reduces the effective concentration of the agonist ATP(4-) at the high- and low-affinity ATP activation site of the hP2XR, and (ii) direct allosteric inhibition of the hP2X7R channel opening that follows ATP(4-) binding to the low-affinity activation site. Due to the hampered activation via the low-affinity activation site, a low pH (as observed in inflamed tissues) leads to a relative increase in the contribution of the high-affinity activation site for hP2X7R channel opening. (C) 2010 Elsevier B.V. All rights reserved.
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