Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

Abstract

Edited by Maurice Montal Keywords:CaV2.2 CRMP-2 Interaction Cdk5 RhoK Phosphorylation a b s t r a c tThe axon/dendrite specification collapsin response mediator protein-2 (CRMP-2) bidirectionally regulates N-type voltage-gated Ca 2+ channels (CaV2.2). But how cyclin dependent kinase 5 (Cdk5)-mediated phosphorylation of CRMP-2 affects its interaction/regulation with CaV2.2 is unknown. CRMP-2-mediated enhancement of currents via CaV2.2 was not observed with a Cdk5 phospho-null CRMP-2-S522A mutant or in cells expressing an inactive Cdk5. Concomitant knockdown of endogenous CRMP2 and overexpression of CRMP2-S522A mutant refractory to knockdown phenocopied the reduction in Ca 2+ influx while the Rho kinase CRMP2-T555A mutant was ineffective. Cdk5-phosphorylated CRMP-2 had increased association with CaV2.2. These results identify an important role for Cdk5 in CRMP2-mediated CaV2.2 regulation. Structured summary of protein interactions:Gsk3b phosphorylates Crmp2by phosphatase assay (View interaction) Crmp2 physically interacts with Cav2.2 by anti tag coimmunoprecipitation (View interaction)

Hierarchical CRMP2 posttranslational modifications control NaV1.7 function

“…3B). Rheobase, the current required to initiate an action potential, was increased in cells expressing the Cdk5 phospho-null CRMP2; however, interpretation of this result as dependent on CRMP2 SUMOylation status or NaV1.7 trafficking is made difficult by previously described relationships between CRMP2 phosphorylation by Cdk5 and modulation of N-type voltage-gated calcium (CaV2.2) channels that may also modulate rheobase (22) (Fig. 3C).…”

SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons

“…[3][4][5] A CRMP2/CaV2.2 complex was observed in sensory neurons; 4 the interaction was enhanced in an activity-dependent fashion implying dynamic regulation. 3 Facile phosphorylation of CRMP2 increased its association with CaV2.2 6 further supporting the importance of a "tunable" interaction, especially in light of findings that disruption of the CRMP2/CaV2. 2 …”

Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

“…Indeed, overexpression of wild-type CRMP2 caused increase in Ca 2C current, while overexpression of CRMP2S522A, a non-phosphorylated CRMP2 mutant, did not increase currents above levels in hippocampal neurons. 67 These findings suggest that Sema3A activates the voltage-gated Ca 2C channel(s) through its enhanced interaction with the phosphorylated CRMP2 by Cdk5.…”

“…36,70 The in vitro phosphorylated CRMP2 at Ser522 was shown to enhance its interaction with Cav2.2. 67 This enhanced interaction between CRMP2 and Cav2.2 was associated with an activation of Cav2.2. Indeed, overexpression of wild-type CRMP2 caused increase in Ca 2C current, while overexpression of CRMP2S522A, a non-phosphorylated CRMP2 mutant, did not increase currents above levels in hippocampal neurons.…”

“…One plausible mechanism is that Sema3A signaling may involve the interaction between CRMP2 and Cav2.2, a voltage-gated calcium channel belonging to the Cav2 family. 67,68 The Cav2 family includes channels containing a 1A , a 1B and a 1E , which mediate P/2 type, N-type, and R-type Ca 2C currents, respectively. 69 Sema3A activates Cdk5, which phosphorylates CRMP2 at Ser522.…”