Voltage-gated calcium channels

Category: membrane

Overview

L-type Cav1.x channels carry inward Ca²⁺ in cardiac + vascular smooth muscle (phase 2 plateau + vasoconstriction). Dihydropyridines (amlodipine, nifedipine, felodipine, nicardipine, isradipine, nimodipine) preferentially block vascular L-type → vasodilation; reflex tachycardia tempered by long-acting kinetics. Non-dihydropyridines (verapamil phenylalkylamine + diltiazem benzothiazepine) hit cardiac + vascular L-type → AV block + negative inotropy + vasodilation; antiarrhythmic class IV. T-type Cav3.x (ethosuximide) underlies thalamic 3-Hz spike-wave absence seizures. α2δ subunits (gabapentin / pregabalin) modulate channel assembly; gabapentinoids reduce neurotransmitter release at presynaptic terminals.

Organ Systems

• cardiovascular
• nervous

Pathway Steps

1. depolarization → l-type-calcium-influx — via Cav1.2 (cardiac/smooth muscle) or Cav1.3 (sinoatrial) opening. Membrane depolarization opens voltage-gated L-type calcium channels (Cav1.x), the dominant Ca²⁺ entry route in cardiac and vascular smooth muscle. These channels are the target of the dihydropyridine and non-dihydropyridine calcium-channel blockers used for hypertension and angina.
2. l-type-calcium-influx → cytosolic-calcium-rise — via cytoplasmic Ca²⁺ activates contraction (muscle) or release (Ca²⁺-induced Ca²⁺ release in cardiac SR). Calcium entering through L-type channels raises cytosolic Ca²⁺, triggering contraction (and, in the heart, calcium-induced calcium release from the SR). Blocking this influx relaxes vascular smooth muscle and reduces cardiac contractility/rate — the therapeutic effect of CCBs.

Known Modulators

• amlodipine (inhibitor) — L-type Cav1.2 (vascular). long-acting dihydropyridine; vascular-selective; daily dosing; first-line HTN
• nifedipine (inhibitor) — L-type Cav1.2 (vascular). first dihydropyridine; short-acting IR form caused reflex tachycardia + ischemia (withdrawn); ER form used in HTN + Raynaud
• felodipine (inhibitor) — L-type Cav1.2 (vascular). dihydropyridine; CYP3A4 substrate (grapefruit DDI 4× AUC documented Bailey 1991)
• nicardipine (inhibitor) — L-type Cav1.2 (vascular). dihydropyridine; IV use in hypertensive emergencies + ICU BP control
• isradipine (inhibitor) — L-type Cav1.2 (vascular). dihydropyridine; mild PD-protection signal in early studies (negative phase 3 STEADY-PD III 2020)
• nimodipine (inhibitor) — L-type Cav1.2 (cerebral vasculature). CNS-penetrant dihydropyridine; SAH-vasospasm prophylaxis indication
• verapamil (inhibitor) — L-type Cav1.2 (cardiac + vascular). phenylalkylamine; cardiac-dominant — AV nodal blocker (SVT rate control); CYP3A4 inhibitor (DDI hot spot with statins/midazolam authored Wave 2a v1.1)
• diltiazem (inhibitor) — L-type Cav1.2 (cardiac + vascular). benzothiazepine; intermediate cardiac/vascular profile; CYP3A4 inhibitor
• ethosuximide (inhibitor) — T-type Cav3.x (thalamic). absence seizure first-line; blocks low-threshold 3-Hz spike-wave oscillator
• gabapentin (inhibitor) — α2δ-1 subunit (presynaptic Ca channel). reduces glutamate/substance-P release at primary afferent terminals; neuropathic pain + restless legs + adjunct seizures
• pregabalin (inhibitor) — α2δ-1 subunit. higher-affinity α2δ ligand vs gabapentin; linear PK (no saturable absorption); generalized anxiety + fibromyalgia + neuropathic pain

References

• PMID 21746798