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Published on: November 11, 2016
Niflumic acid blocks native and recombinant T-type channels
Enrique Balderas1, Rogelio Ateaga-Tlecuitl, Manuel Rivera
1Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Avenida Universidad 2001, Col. Chamilpa, Cuernavaca Mor., Mexico.
Journal of Cellular Physiology
|September 8, 2011
Summary
Niflumic acid blocks T-type calcium channels in mouse sperm, aiding research into calcium channel roles in fertilization. This study identifies Ca(V)3.1 channels as key players in sperm function.
Area of Science:
- Spermatogenesis and Fertilization Biology
- Molecular and Cellular Physiology
- Pharmacology of Ion Channels
Background:
- Voltage-dependent calcium channels (CaV) are crucial for sperm functions like motility and acrosome reaction (AR).
- T-type calcium channels (CaV3) are implicated in the AR, but their specific roles and isoforms in sperm remain unclear.
- Niflumic acid (NA), an anti-inflammatory drug, is known to block T-currents and chloride channels in sperm.
Purpose of the Study:
- To investigate the mechanism of niflumic acid (NA) blockade on T-type calcium channels in mouse spermatogenic cells.
- To determine if NA can differentiate between CaV3 channel isoforms (CaV3.1, CaV3.2, CaV3.3) in sperm.
- To elucidate the specific CaV3 isoform responsible for T-type currents in mouse spermatogenic cells.
Main Methods:
- Electrophysiological patch-clamp recordings in isolated mouse spermatogenic cells and HEK cells expressing CaV3 isoforms.
- Pharmacological analysis of niflumic acid (NA) blockade kinetics and voltage-dependence.
- Molecular docking simulations to predict NA binding sites on CaV3 channels.
Main Results:
- Niflumic acid (NA) effectively blocks T-type currents in mouse spermatogenic cells with an IC50 of 73.5 µM.
- NA blockade is state-dependent, being more potent on open and inactivated channels.
- Heterologously expressed CaV3.1 and CaV3.3 channels show higher sensitivity to NA than CaV3.2, and NA slows recovery from inactivation for all three isoforms.
- Molecular docking suggests NA binds to the extracellular side of CaV3.1.
- Spermatogenic cell T-type currents resemble CaV3.1 in biophysical properties and NA sensitivity.
Conclusions:
- Niflumic acid (NA) is a valuable tool for studying T-type calcium channels in sperm.
- Mouse spermatogenic cell T-type currents share characteristics with CaV3.1 channels.
- Despite CaV3.1 null mice retaining T-currents, the data suggest CaV3.1's significant role, potentially with compensatory mechanisms or involvement of other isoforms like CaV3.2.
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