Neuronal voltage-gated N-type (Cav2.2) calcium channels are expressed throughout the nervous system and regulate neurotransmitter release and hence synaptic transmission. They are predominantly modulated via G protein-coupled receptor activated pathways, and the well characterized Gβγ subunits inhibit Cav2.2 currents. Analgesic α-conotoxin Vc1.1, a peptide from predatory marine cone snail venom, inhibits Cav2.2 channels by activating pertussis toxin-sensitive Gi/o proteins via the GABAB receptor (GABABR) and potently suppresses pain in rat models. Using a heterologous GABABR expression system, electrophysiology, and mutagenesis, we showed α-conotoxin Vc1.1 modulates Cav2.2 via a different pathway from that of the GABABR agonists GABA and baclofen. In contrast to GABA and baclofen, Vc1.1 changes Cav2.2 channel kinetics by increasing the rate of activation and shifting its halfmaximum inactivation to a more hyperpolarized potential. We then systematically truncated the GABAB1a C terminus and discovered that removing the proximal carboxyl terminus of the GABAB1a subunit significantly reduced Vc1.1 inhibition of Cav2.2 currents. We propose a novel mechanism by which Vc1.1 activates GABABR and requires the GABAB1a proximal carboxyl terminus domain to inhibit Cav2.2 channels. These findings provide important insights into how GABABRs mediate Cav2.2 channel inhibition and alter nociceptive transmission.