@article {He1187, author = {Mu-Lan He and Taka-aki Koshimizu and Melanija Tomi{\'c} and Stanko S. Stojilkovic}, title = {Purinergic P2X2 Receptor Desensitization Depends on Coupling between Ectodomain and C-Terminal Domain}, volume = {62}, number = {5}, pages = {1187--1197}, year = {2002}, doi = {10.1124/mol.62.5.1187}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The wild-type P2X2 purinergic receptor (P2X2aR) and its splice form lacking the intracellular Val370-Gln438 C-terminal sequence (P2X2bR) respond to ATP stimulation with comparable EC50 values and peak current/calcium responses but desensitize in a receptor-specific manner. P2X2aR desensitizes slowly and P2X2bR desensitizes rapidly. We studied the effects of different agonists, and of substituting the ectodomain, on the pattern of calcium signaling by P2X2aR and P2X2bR. Both receptors showed similar EC50values (estimated from the peak calcium response) and IC50values (estimated from the rate of calcium signal desensitization) for agonists, in the order 2-MeS-ATP <= ATP <= ATPγS \< BzATP << αβ-meATP, and the IC50 values for agonists were shifted to the right compared with their EC50 values. Furthermore, the ATP-induced receptor-subtype specific pattern of desensitization was mimicked by high- but not by low-efficacy agonists, suggesting a ligand-specific desensitization pattern. To test this hypothesis, we generated chimeric P2X2aR and P2X2bR containing the Val60-Phe301ectodomain sequence of P2X3R and Val61-Phe313 ectodomain sequence of P2X7R instead the native Ile66-Tyr310 sequence. The mutated P2X2a+X3R and P2X2b+X3R exhibited comparable EC50 values for ATP, BzATP, and αβ-meATP in the submicromolar concentration range and desensitized in a receptor-specific and ligand-nonspecific manner. On the other hand, the chimeric P2X2+X7R exhibited decreased sensitivity for ATP and desensitized in a receptor-nonspecific manner. These results suggest that efficacy of agonists for the ligand-binding domain of P2X2Rs reflects the strength of desensitization controlled by their C-terminal structures.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/62/5/1187}, eprint = {https://molpharm.aspetjournals.org/content/62/5/1187.full.pdf}, journal = {Molecular Pharmacology} }