Linopirdine is a competitive antagonist of alpha9alpha10 containing nicotinic ACh receptors

GÓMEZ-CASATI, ME; KATZ E; LIOUDYNO, ML; PARAMESHWARAN-IYER S; FUCHS PA; ELGOYHEN, AB

Daytona Beach, FL, USA

Congreso; The Association for Research in Otolaryngology, midwinter meeting; 2003

Studies of the electrophysiological response to ACh in mammalian outer hair cells (OHCs) are hindered by the presence of a large potassium current (IK,n). Since IK,n can be blocked by linopirdine, cholinergic effects might be better revealed in the presence of this compound. However, initial attempts to use linopirdine suggested it may also affect the hair cell’s cholinergic response. In inner hair cells IHCs (P7-12) recorded in excised apical turns of the rat cochlea, responses to 100 μM ACh were reduced 40% by 100 μM linopirdine, both at –90 and –40mV. In OHCs (P28-30) ACh responses at –30 mV were reduced by 50%. Linopirdine could be acting on either the ACh receptor (alpha9alpha10) and/or the SK potassium channels underlying the hair cell’s ACh response. We tested the effects of linopirdine on recombinant alpha9alpha10 ACh receptors expressed in Xenopus laevis oocytes. Currents evoked by 100 M ACh (Vhold: -70 mV) were reduced by linopirdine in a concentration-dependent manner (IC50 5.3 uM). This reduction was reversible and voltage-independent. Using increasing concentrations of ACh in the presence of 10 M linopirdine, we found a parallel rightward shift with an increment in the EC50 value (EC50 = 13.8 uM for ACh and 382.5 uM for ACh + 10 uM linopirdine). No change in the maximal response was observed, suggesting a competitive mechanism of block. Thus, linopirdine interacts with alpha9alpha10 receptors, and must be employed with caution when studying the hair cell’s response to ACh.