Proton-independent activation of acid-
sensing ion channel 3 by an alkaloid,
lindoldhamine, from Laurus nobilis
Alexander I Sobolevsky, Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th
Street, New York, NY 10032, USA, and Sergey A Kozlov, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of
Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia. E-mail: firstname.lastname@example.org; email@example.com
22 June 2017;
5 December 2017;
7 December 2017
Dmitry I Osmakov
* , Sergey G Koshelev
*, Yaroslav A Andreev
, Maxim A Dubinnyi
Vadim S Kublitski
, Alexander I Sobolevsky
and Sergey A Kozlov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia,
Institute of Molecular Medicine,
Sechenov First Moscow State Medical University, Moscow, Russia, and
Department of Biochemistry and Molecular Biophysics, Columbia University,
New York, NY, USA
*These authors contributed equally to this work.
BACKGROUND AND PURPOSE
Acid-sensing ion channels (ASICs) play an important role in synaptic plasticity and learning, as well as in nociception and
mechanosensation. ASICs are involved in pain and in neurological and psychiatric diseases, but their therapeutic potential is
limited by the lack of ligands activating them at physiological pH.
We extracted, puriﬁed and determined the structure of a bisbenzylisoquinoline alkaloid, lindoldhamine, (LIN) from laurel leaves.
Its effect on ASIC3 channels were characterized, using two-electrode voltage-clamp electrophysiological recordings from Xenopus
At pH 7.4 or higher, LIN activated a sustained, proton-independent, current through rat and human ASIC3 channels, but not rat
ASIC1a or ASIC2a channels. LIN also potentiated proton-induced transient currents and promoted recovery from desensitization
in human, but not rat, ASIC3 channels.
CONCLUSIONS AND IMPLICATIONS
We describe a novel ASIC subtype-speciﬁc agonist LIN, which induced proton-independent activation of human and rat ASIC3
channels at physiological pH. LIN also acts as a positive allosteric modulator of human, but not rat, ASIC3 channels. This unique,
species-selective, ligand of ASIC3, opens new avenues in studies of ASIC structure and function, as well as providing new ap-
proaches to drug design.
ASIC, acid-sensing ion channel; GMQ, 2-guanidine-4-methylquinazoline
British Journal of
British Journal of Pharmacology (2018) 175 924–937 924
DOI:10.1111/bph.14134 © 2017 The British Pharmacological Society