Background and Purpose
Transmembrane Cav2.2 (N-type) voltage-gated calcium
channels are genetically and pharmacologically validated pain targets.
Clinical block of Cav2.2 (e.g., with Prialt) or indirect
modulation (e.g., with gabapentinoids) mitigates chronic pain but is
constrained by side effects. The cytosolic auxiliary subunit collapsin
response mediator protein 2 (CRMP2) targets Cav2.2 to
the sensory neuron membrane and regulates their function. A
CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2
interaction to inhibit calcium influx, transmitter release and pain.
Homology-guided mutagenesis of CBD3 revealed an antinociceptive core at
A1RSR4. Here, the
A1R2 CBD3 dipeptide was identified as
critical for Cav2.2 molecular recognition and served as
a scaffold for identification of small molecule peptidomimetic
allosteric regulators of Cav2.2.