TY - JOUR T1 - Differential Modulation of β2 and β4 Subunits of Human Neuronal Nicotinic Acetylcholine Receptors by Acidification JF - Molecular Pharmacology JO - Mol Pharmacol SP - 347 LP - 355 DO - 10.1124/mol.66.2.347 VL - 66 IS - 2 AU - Galya Abdrakhmanova AU - Lars Cleemann AU - Jon Lindstrom AU - Martin Morad Y1 - 2004/08/01 UR - http://molpharm.aspetjournals.org/content/66/2/347.abstract N2 - We have shown previously that acidification increases the affinity of agonists to rat α3β4 nicotinic acetylcholine receptors (nAChR) and accelerates both the activation and decay kinetics of agonist-induced currents recorded from human embryonic kidney 293 cells stably expressing the receptor (Abdrakhmanova et al., 2002b). Here, we report on experiments examining the effect of rapid acidification on four different subtypes (α3β4α5, α4β2, α3β2, and α3β2α5) of human neuronal nAChRs stably expressed in tsA201 cells using a piezoelectric device for rapid (<5 ms) solution application. Application of ACh, at its EC50 concentration for each nAChR subtype, at pH values 7.4 and 6.0, showed that acidification, similarly to that reported for rat α3β4 acetylcholine receptors (AChRs), increased the amplitude and accelerated the activation and decay kinetics of the currents in human α3β4α5 AChRs by increasing their affinity to the agonist. In sharp contrast, acidification reduced the amplitude but accelerated the decay kinetics of the current in all human β2-containing nAChR subtypes (α3β2, α3α5β2, α4β2) examined in this study. Brief application of ACh at saturating concentration (1 mM) on α3β4α5 AChRs induced a “rebound current” upon rapid washout of the agonist at pH 7.4, but no “rebound current” was observed in α3β2 AChRs. Surprisingly, acidification, pH 6.0, applied only during the agonist pulse also accelerated the decay kinetics of the “rebound current”. Our data provide evidence for the specificity of proton-induced modulation of neuronal nAChRs based on their β subunit composition. Furthermore, in α3β4α5 AChR, we find that protonation effects may persist, after washout of acidic solutions, consistent with proton-induced conformational changes of the receptor. ER -