Mechanism of Action of Gabapentin
Gabapentin binds with high affinity to the α2δ subunit (specifically α2δ-1 and α2δ-2) of voltage-gated calcium channels, which inhibits excitatory neurotransmitter release, though the precise molecular mechanisms remain incompletely defined. 1
Primary Mechanism
- Gabapentin binds to the α2δ subunit of voltage-activated calcium channels, with greater affinity for α2δ-1 than α2δ-2 and no affinity for the α2δ-3 subunit 2, 3
- This binding reduces calcium influx and decreases synaptic neurotransmitter release into hyperexcited neurons 3
- The FDA label confirms this high-affinity binding, though explicitly states that the relationship of this binding to therapeutic effects remains unknown 1
What Gabapentin Does NOT Do
Despite being structurally designed as a GABA analog, gabapentin has several important negative characteristics:
- Does NOT act as an agonist at GABAA or GABAB receptors 2, 1
- Does NOT affect GABA binding, uptake, or degradation 1
- Does NOT significantly affect GABA levels (though some research suggests it may increase GABA concentration and synthesis rate in brain tissue) 2, 4
- Does NOT cross the blood-brain barrier like GABA, but penetrates the CNS through the large neutral amino acid transporter (system L) 5, 4
Time Course of Action
A critical but often overlooked aspect of gabapentin's mechanism:
- Gabapentin requires chronic exposure (17-20 hours) to inhibit calcium currents effectively 6
- Acute application produces little to no effect on calcium currents in multiple experimental systems 6, 7
- This suggests gabapentin acts primarily at an intracellular location after cellular uptake, disrupting the trafficking of α2δ subunits and calcium channels 6
Additional Proposed Mechanisms
While the α2δ binding is the most established mechanism, research has identified other potential actions:
- Competes with branched-chain amino acids (leucine, isoleucine, valine, phenylalanine) for transport via system L 4
- May reduce release of monoamine neurotransmitters 4
- May modulate glutamate release through voltage-sensitive calcium channel inhibition 5
- Does NOT directly affect voltage-dependent sodium channels, NMDA receptors, or non-NMDA receptors at therapeutic concentrations 7
Clinical Implications
- All pharmacological actions are due to the parent compound—gabapentin is not appreciably metabolized in humans 1
- The mechanism explains why gabapentin is effective across multiple conditions (neuropathic pain, seizures, anxiety) despite different pathophysiologies 3, 5
- The requirement for chronic exposure may explain delayed onset of therapeutic effects in clinical practice 6