Arachidonic acid and prostaglandin D2 cooperatively accelerate desensitization of nicotinic acetylcholine receptor channel in mouse skeletal muscles.
To clarify the effects of arachidonic acid (AA) and its metabolites on desensitization of nicotinic acetylcholine (ACh) receptor channel in mouse skeletal muscle cells, we investigated the time-dependent decrease in the channel opening frequency of ACh (1 microM)-activated channel currents by the cell-attached patch clamp technique. AA (30-100 microM) applied to a patched membrane or to non-patched membrane accelerated the decrease in the channel opening frequency. A cyclooxygenase inhibitor, indomethacin (10 microM), prevented the acceleration elicited by 30 microM AA, but not by 100 microM AA. A lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), and a cytochrome P-450 inhibitor, ketoconazole (3 microM), did not affect the acceleration by 30 microM AA. Prostaglandin (PG) D2 at 10 microM alone and at 25 nM in combination with 10 microM AA accelerated the decrease in the channel opening frequency. No acceleration was observed with PGE2 at 10 microM alone and at 25 nM in combination with 10 microM AA. Pretreatment with a protein kinase (PK) C inhibitor, staurosporine (10 nM), but not with a PKA inhibitor, H-89 (3 microM), prevented the acceleration elicited by AA + PGD2. These results suggest that AA, and PGD2 of its metabolites, cooperatively accelerate desensitization of nicotinic ACh receptor channel. The activation of PKC by AA and PGD2 may be involved in the mechanism of the cooperative acceleration of desensitization.
Nojima
H
H
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan. yakusaku@ms.toyama-mpu.ac.jp
Sasaki
T
T
Kimura
I
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007473:Ion Channels; D011978:Receptors, Nicotinic; D016718:Arachidonic Acid; D011493:Protein Kinase C; D019311:Staurosporine; D000109:Acetylcholine; D015230:Prostaglandin D2