Pesti, Krisztina and Lukács, Péter and Mike, Árpád (2019) Type I like behavior of the type II alpha 7 nicotinic acetylcholine receptor positive allosteric modulator A-867744. PEERJ, 7. ISSN 2167-8359
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Abstract
Cognitive impairment often involves the decreased expression or hypofunction of alpha 7-type nicotinic acetylcholine receptors (alpha 7 nAChRs). Agonists or positive allosteric modulators (PAMs) of alpha 7 nAChRs are known to be potential treatments for dementias, different neurodegenerative disorders, pain syndromes and conditions involving inflammation. In some of these conditions, it is desirable to maintain the temporal precision of fast cholinergic events, while in others, this temporal precision is unnecessary. For this reason, the optimal therapeutic effect for distinct indications may require PAMs with different mechanisms of action. The two major mechanisms are called "type I", which are compounds that augment alpha 7 nAChR-mediated currents but maintain their characteristic fast kinetics; and "type II", which are compounds that produce augmented and prolonged currents. In this study, we performed a kinetic analysis of two type II PAMs of the alpha 7 nAChR: PNU-120596 and A-867744, using a fast perfusion method that allowed high temporal resolution. We characterized the type of modulation produced by the two compounds, the state-dependence of the modulatory action, and the interaction between the two compounds. We found fundamental differences between the modulation mechanisms by PNU-120596 and A-867744. Most importantly, during brief agonist pulses, A-867744 caused a strikingly type I-like modulation, while PNU-120596 caused a type II-like prolonged activation. Our results demonstrate that specific compounds, even though all labeled as type II PAMs, can behave in completely different ways, including their onset and offset kinetics, state preference, and single channel open time. Our results emphasize that subtle details of the mechanism of action may be significant in assessing the therapeutic applicability of alpha 7 nAChR PAM compounds.
Item Type: | Article |
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Additional Information: | Funding Agency and Grant Number: Hungarian Brain Research Program [KTIA-NAP-132-2014-002]; Hungary's Economic Development and Innovation Operative Programme [GINOP-2.3.2-15-2016-00051] Funding text: This work was supported by the Hungarian Brain Research Program (KTIA-NAP-132-2014-002), and by Hungary's Economic Development and Innovation Operative Programme (GINOP-2.3.2-15-2016-00051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
Uncontrolled Keywords: | Choline; patch clamp; POSITIVE ALLOSTERIC MODULATOR; cognitive enhancement; PNU-120596; alpha 7 nAChR; A-867744; Type II PAM; |
Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3020 Biophysics / biofizika R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 20 Oct 2019 03:58 |
Last Modified: | 20 Oct 2019 03:58 |
URI: | http://real.mtak.hu/id/eprint/102525 |
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