Related Experiment Video
Updated: Aug 19, 2026
Real-time Evaluation of Absolute, Cytosolic, Free Ca2+ and Corresponding Contractility in Isolated, Pressurized Lymph Vessels
Published on: March 22, 2024
Contrasting the effects of nifedipine on subtypes of endogenous and recombinant T-type Ca2+ channels
Alexander Shcheglovitov1, Tatiana Zhelay, Yulia Vitko
1International Center of Molecular Physiology, National Academy of Sciences of Ukraine, Bogomoletz St. 4, Kyiv-24, Ukraine.
Abstract:
There is evidence that nifedipine (Nif) - a dihydropyridine (DHP) Ca(2+)-channel antagonist mostly known for its L-type-specific action--is capable of blocking low voltage-activated (LVA or T-type) Ca(2+) channels as well. However, the discrimination by Nif of either various endogenous T-channel subtypes, evident from functional studies, or cloned Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 T-channel alpha 1 subunits have not been determined. Here, we investigated the effects of Nif on currents induced by Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 expression in Xenopus oocytes or HEK-293 cells (I(alpha 1G), I(alpha 1H) and I(alpha 1I), respectively) and two kinetically distinct, "fast" and "slow", LVA currents in thalamic neurons (I(LVA,f) and I(LVA,s)). At voltages of the maximums of respective currents the drug most potently blocked I(alpha 1H) (IC(50)=5 microM, max block 41%) followed by I(alpha 1G) (IC(50)=109 microM, 23%) and I(alpha 1I) (IC(50)=243 microM, 47%). The mechanism of blockade included interaction with Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 open and inactivated states. Nif blocked thalamic I(LVA,f) and I(LVA,s) with nearly equal potency (IC(50)=22 microM and 28 microM, respectively), but with different maximal inhibition (81% and 51%, respectively). We conclude that Ca(v)3.2 is the most sensitive to Nif, and that quantitative characteristics of drug action on T-type Ca(2+) channels depend on cellular system they are expressed in. Some common features in the voltage- and state-dependence of Nif action on endogenous and recombinant currents together with previous data on T-channel alpha 1 subunits mRNA expression patterns in the thalamus point to Ca(v)3.1 and Ca(v)3.3 as the major contributors to thalamic I(LVA,f) and I(LVA,s), respectively.
Insights
Nifedipine (Nif) blocks T-type calcium channels, with Ca(v)3.2 being the most sensitive. The drug
Area of Science:
- Pharmacology
- Neuroscience
- Molecular Biology
Background:
- Nifedipine (Nif), a dihydropyridine (DHP) calcium channel antagonist, is primarily known for its L-type calcium channel specificity.
- Emerging evidence suggests Nif can also block low voltage-activated (LVA), or T-type, calcium channels.
- The precise selectivity of Nif across different T-type channel subtypes (Ca(v)3.1, Ca(v)3.2, Ca(v)3.3) and their endogenous counterparts remains undetermined.
Purpose of the Study:
- To investigate the effects of Nifedipine (Nif) on cloned T-type calcium channel alpha 1 subunits (Ca(v)3.1, Ca(v)3.2, Ca(v)3.3).
- To determine the potency and mechanism of Nif blockade on endogenous fast and slow LVA currents in thalamic neurons.
- To elucidate the relative sensitivity of different T-type calcium channel subtypes to Nif.
Main Methods:
- Functional expression of Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3 alpha 1 subunits in Xenopus oocytes and HEK-293 cells.
- Electrophysiological recordings of currents induced by cloned T-type channels (I(alpha 1G), I(alpha 1H), I(alpha 1I)).
- Voltage-clamp analysis of Nif's effects on endogenous fast and slow LVA currents (I(LVA,f), I(LVA,s)) in thalamic neurons.
Main Results:
- Nifedipine most potently blocked I(alpha 1H) (IC(50)=5 microM), followed by I(alpha 1G) (IC(50)=109 microM) and I(alpha 1I) (IC(50)=243 microM).
- Nif blockade involved interaction with open and inactivated states of Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3 channels.
- In thalamic neurons, Nif blocked I(LVA,f) (IC(50)=22 microM, 81% max block) and I(LVA,s) (IC(50)=28 microM, 51% max block).
Conclusions:
- Ca(v)3.2 is the T-type calcium channel subtype most sensitive to Nifedipine.
- The quantitative effects of Nifedipine on T-type calcium channels are dependent on the cellular expression system.
- Ca(v)3.1 and Ca(v)3.3 likely contribute significantly to thalamic I(LVA,f) and I(LVA,s), respectively.
Related Concept Videos
01:25Antianginal Drugs: Calcium Channel Blockers and Ranolazine
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
01:18Antihypertensive Drugs: Action of Calcium Channel Blockers
01:20Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
01:26Adrenergic Receptors: β Subtype
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...
01:22Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
01:31Adrenergic Receptors: ɑ Subtype
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...