Homology‐guided mutational analysis reveals the functional requirements for antinociceptive specificity of collapsin response mediator protein 2‐derived peptides

Background and Purpose N‐type voltage‐gated calcium (Cav2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav2.2 channel antagonists are recommended as first‐line treatment for neuropathic pain, calcium‐current blocking gabapentinoids inadequately alleviate chronic pain symptoms and often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets Cav2.2 channels to the sensory neuron membrane and allosterically modulates their function. A 15‐amino‐acid peptide (CBD3), derived from CRMP2, disrupts the functional protein–protein interaction between CRMP2 and Cav2.2 channels to inhibit calcium influx, transmitter release and acute, inflammatory and neuropathic pain. Here, we have mapped the minimal domain of CBD3 necessary for its antinociceptive potential.