RT Journal Article
SR Electronic
T1 Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.093179
DO 10.1124/mol.114.093179
A1 Walrati Limapichat
A1 Dennis A. Dougherty
A1 Henry A. Lester
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/06/24/mol.114.093179.abstract
AB P2X receptors (P2XRs) and nicotinic acetylcholine receptors (nAChRs) display functional and physical interactions in many cell types and heterologous expression systems, but interactions between α6β4-containing (α6β4*) nAChRs and P2X2Rs and /or P2X3Rs have not been fully characterized. In oocytes co-expressing α6β4 nAChRs and P2X2Rs, P2X3Rs, or P2X2/3Rs, we measured several types of crosstalk. A novel form of crosstalk occurs between α6β4 nAChRs and P2X2Rs. P2X2Rs were forced into a prolonged desensitized state upon activation by ATP through a mechanism that does not depend on the intracellular C-terminus of the P2X2Rs. Co-expression of α6β4 nAChRs and P2X3Rs shifts the P2X3 dose-response relation to the right, even in the absence of acetylcholine (ACh). Moreover, when ACh and ATP are co-applied, currents become non-additive, as previously reported for other Cys-loop receptors interacting with P2XRs, and this crosstalk is dependent on the presence of P2X3 C-terminal domain. P2X2Rs also functionally interact with α6β4β3 but through a different mechanism from α6β4. The interaction with P2X3Rs is less pronounced for the α6β4β3 than the α6β4 nAChR. We also measured a functional interaction between the α6β4 nAChRs and the heteromeric P2X2/3R. Experiments with the nAChR channel blocker mecamylamine on P2X2 - α6β4 oocytes point to the loss of P2X2 channel activity during the crosstalk, while for P2X2 - α6β4β3, P2X2/3 - α6β4 and P2X2/3 - α6β4β3 the ion channel pores of the P2XRs were fully functional and unaltered by the receptor interaction. These results may be relevant to dorsal root ganglion cells and to other neurons which co-express these receptor subunits.