TY - JOUR
T1 - The dual effect of PNU-120596 on α7 nicotinic acetylcholine receptor channels
AU - Kalappa, Bopanna I.
AU - Uteshev, Victor V.
N1 - Funding Information:
This work was supported by the NIH grant DK082625 to VU. We thank the NIH NIDA Research Resources Drug Supply Program for PNU-120596; Dr. Nathalie Sumien for advice on statistical analysis and Dr. Eric Gonzales for discussion of mechanisms of open channel block.
PY - 2013
Y1 - 2013
N2 - PNU-120596 (1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea) , a Type-II positive allosteric modulator of α7 nicotinic acetylcholine receptors inhibits α7 desensitization and robustly prolongs openings of α7 channels. However, these effects may render α7 channels more accessible to positively charged molecules and thus, more susceptible to voltage-dependent open-channel-block-like inhibition. To test this hypothesis, choline chloride (i.e., choline), a selective endogenous α7 agonist, and bicuculline methochloride (i.e., bicuculline), a competitive α7 antagonist, were used as membrane voltage-sensitive probes in whole-cell voltage-clamp recordings from hippocampal CA1 interneurons in acute brain slices in the absence and presence of PNU-120596. PNU-120596 enhanced voltage-dependent inhibition of α7 responses by bicuculline and choline. In the presence of PNU-120596, α7 channels favored a burst-like kinetic modality in the presence, but not absence of bicuculline and bursts of α7 openings were voltage-dependent. These results suggest that PNU-120596 alters the pharmacology of α7 channels by making these channels more susceptible to voltage-dependent inhibitory interactions with positively charged drugs at concentrations that do not potently inhibit α7 channels without PNU-120596. This inhibition imitates α7 nicotinic receptor desensitization and compromises the potentiating anti-desensitization effects of PNU-120596 on α7 nicotinic receptors. This unexpected dual action of PNU-120596, and possibly other Type-II positive allosteric modulators of α7 nicotinic receptors, may lead to unanticipated α7 channel-drug interactions and misinterpretation of α7 single-channel data.
AB - PNU-120596 (1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea) , a Type-II positive allosteric modulator of α7 nicotinic acetylcholine receptors inhibits α7 desensitization and robustly prolongs openings of α7 channels. However, these effects may render α7 channels more accessible to positively charged molecules and thus, more susceptible to voltage-dependent open-channel-block-like inhibition. To test this hypothesis, choline chloride (i.e., choline), a selective endogenous α7 agonist, and bicuculline methochloride (i.e., bicuculline), a competitive α7 antagonist, were used as membrane voltage-sensitive probes in whole-cell voltage-clamp recordings from hippocampal CA1 interneurons in acute brain slices in the absence and presence of PNU-120596. PNU-120596 enhanced voltage-dependent inhibition of α7 responses by bicuculline and choline. In the presence of PNU-120596, α7 channels favored a burst-like kinetic modality in the presence, but not absence of bicuculline and bursts of α7 openings were voltage-dependent. These results suggest that PNU-120596 alters the pharmacology of α7 channels by making these channels more susceptible to voltage-dependent inhibitory interactions with positively charged drugs at concentrations that do not potently inhibit α7 channels without PNU-120596. This inhibition imitates α7 nicotinic receptor desensitization and compromises the potentiating anti-desensitization effects of PNU-120596 on α7 nicotinic receptors. This unexpected dual action of PNU-120596, and possibly other Type-II positive allosteric modulators of α7 nicotinic receptors, may lead to unanticipated α7 channel-drug interactions and misinterpretation of α7 single-channel data.
KW - Bicuculline
KW - Channel block
KW - Choline
KW - Desensitization
KW - PNU-120596
KW - PNU120596
KW - α Nicotinic receptor
UR - http://www.scopus.com/inward/record.url?scp=84887075134&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2013.08.027
DO - 10.1016/j.ejphar.2013.08.027
M3 - Article
C2 - 24036349
AN - SCOPUS:84887075134
SN - 0014-2999
VL - 718
SP - 226
EP - 234
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -