The P2X7 receptor (P2X7R) is a ligand-gated ion channel that conducts Na(+), K(+), and Ca(2+) when activated by extracellular ATP. In various cell types, such as secretory epithelia, the P2X7R is co-expressed with Ca(2+)-dependent Cl(-) channels of the TMEM16/anoctamin family. Here, we studied whether the P2X7R and TMEM16A/anoctamin-1 (Ano1) or TMEM16F/anoctamin-6 (Ano6) interact functionally and physically, using oocytes of Xenopus laevis and Ambystoma mexicanum (Axolotl) for heterologous expression. As a control, we co-expressed anoctamin-1 with the P2Y1 receptor (P2Y1R), which induces the release of Ca(2+) from intracellular stores via activating phospholipase C through coupling to Gαq. We found that co-expression of anoctamin-1 with the P2Y1R resulted in a small transient increase in Cl(-) conductance in response to ATP. Co-expression of anoctamin-1 with the P2X7R resulted in a large sustained increase in Cl(-) conductance via Ca(2+) influx through the ATP-opened P2X7R in Xenopus and in Axolotl oocytes, which lack endogenous Ca(2+)-dependent Cl(-) channels. P2Y1R- or P2X7R-mediated stimulation of Ano1 was primarily functional, as demonstrated by the absence of a physically stable interaction between Ano1 and the P2X7R. In the pancreatic cell line AsPC-1, we found the same functional Ca(2+)-dependent interaction of P2X7R and Ano1. The P2X7R-mediated sustained activation of Ano1 may be physiologically relevant to the time course of stimulus-secretion coupling in secretory epithelia. No such increase in Cl(-) conductance could be elicited by activating the P2X7 receptor in either Xenopus oocytes or Axolotl oocytes co-expressing Ano6. The lack of function of Ano6 can, at least in part, be explained by its poor cell-surface expression, resulting from a relatively inefficient exit of the homodimeric Ano6 from the endoplasmic reticulum.

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ZusammenfassungViele Medikamente können Myopathien auslösen. Statine sind dabei die häufigste Ursache, aber auch Amiodaron, Chlorochin, antiretrovirale Medikamente, Kortikosteroide und Checkpoint-Inhibitoren sind potentiell myotoxisch. Häufigster nicht-medikamentöser Auslöser ist Alkoholismus. Pathogenetisch spielen unterschiedliche, meist nicht völlig verstandene Mechanismen eine Rolle. Symptome reichen von milden Myalgien und Krampi bis hin zu hochgradigen Paresen, Myoglobinurien und lebensbedrohlicher Rhabdomyolyse. Diagnostisch sind die Anamnese einer Exposition gegenüber Noxen sowie von Risikofaktoren, die klinische Untersuchung, die CK-Wert-Bestimmung und Elektromyographie wegweisend. Eine Muskelbiopsie ist oft für die Diagnosesicherung nötig. Das frühzeitige Erkennen von toxischen Myopathien ist relevant, da eine Beendigung des Auslösers meist zur prompten Symptombesserung führt. Selten wird eine immunvermittelte Muskelschädigung angestoßen, die eine spezifische Immuntherapie erfordert.