The influx of Ca²⁺ through the voltage-gated calcium channels (Ca_v) triggers the fusion of synaptic vesicle with the plasma membrane to release neurotransmitters at the nerve terminals. The binding of calmodulin (CaM) on the IQ motifs at the C-terminals of Ca_v1.1 and Ca_v2.1 is responsible for the Ca²⁺-dependent inactivation (CDI). The Ca_v2.2 is present in the both central and peripheral nervous system, and it has a major presynaptic role in regulation of transmitter release. The Ca_v2.2 has a similar IQ motif with IF as the central amino acids; however, its interaction with CaM has not been well investigated. In this report, Ca_v2.2 and CaM were co-expressed in 293T cells and the Ca²⁺ currents were recorded by patch-clamp technique in whole-cell mode. The inward Ca2+ currents inactivated quickly to 15.5 ± 5.8% of the peak current at 250 ms when co-expressed with CaM. This inactivation was blocked by the co-expressed Ca^{2+-binding deficient mutation CaM₁₂₃₄ to 44.1 ± 5.4%. CaM₁₂ and CaM₃₄ also decreased the Ca2+ dependent inactivation (CDI) to 40%. IF mutations caused a lower current density and shifted the activation curve V_h from 18.5 ± 3.1 mV to 30.5 ± 5.3mV, but had no significant effect on the CDI (19.1 ± 4.2%). When co-expressed with IF mutations, CaM mutations did not affect the gating kinetics of the channels. Although CaM₃₄ and CaM₁₂₃₄ did not change CDI (22.5 ± 5.3/ 23.2 ± 5.8%), CaM₁₂ decreases CDI to 46.6 ± 5.7%. In addition, CaM₁₂ co-expression increased the current density of wild type and IF mutations. Therefore, the N- and C-lobes of CaM play distinct roles in modulating the Ca_v2.2 activities.}