Abstract
Low voltage-activated (LVA) T-type Ca2+ channels activate in response to subthreshold membrane depolarizations and therefore represent an important source of Ca2+ influx near the resting membrane potential. In neurons, these proteins significantly contribute to control relevant physiological processes including neuronal excitability, pacemaking and post-inhibitory rebound burst firing. Three subtypes of T-type channels (Cav3.1 to Cav3.3) have been identified, and using functional expression of recombinant channels diverse studies have validated the notion that T-type Ca2+ channels can be modulated by various endogenous ligands as well as by second messenger pathways. In this context, the present study reveals a previously unrecognized role for cyclin-dependent kinase 5 (Cdk5) in the regulation of native T-type channels in N1E-115 neuroblastoma cells, as well as recombinant Cav3.1channels heterologously expressed in HEK-293 cells. Cdk5 and its co-activators play critical roles in the regulation of neuronal differentiation, cortical lamination, neuronal cell migration and axon outgrowth. Our results show that overexpression of Cdk5 causes a significant increase in whole cell patch clamp currents through T-type channels in N1E-115 cells, while siRNA knockdown of Cdk5 greatly reduced these currents. Consistent with this, overexpression of Cdk5 in HEK-293 cells stably expressing Cav3.1channels upregulates macroscopic currents. Furthermore, using site-directed mutagenesis we identified a major phosphorylation site at serine 2234 within the C-terminal region of the Cav3.1subunit. These results highlight a novel role for Cdk5 in the regulation of T-type Ca2+ channels.
Highlights
The family of voltage-gated Ca2+ (CaV) channels are transmembrane proteins that serves as transducers of cell surface membrane potential changes into local intracellular Ca2+ transients that initiate a myriad of physiological events
The possible role of cyclin-dependent kinase 5 (Cdk5)/p35 on T-type current regulation was supported by using the inhibitor olomoucine (50 μM), which fully prevented the effect of the kinase on the macroscopic currents
Diverse studies have shown that Cdk5 has multiple functions in the developing, adult, and aging brain, and that a change in its localization from the growth cones to the presynaptic terminals is an important mechanism underlying the diversity of functions Cdk5 plays in nerve cells [34],[35],[36]
Summary
The family of voltage-gated Ca2+ (CaV) channels are transmembrane proteins that serves as transducers of cell surface membrane potential changes into local intracellular Ca2+ transients that initiate a myriad of physiological events. Cav3.1 Channel Regulation by Cdk into high voltage-activated (HVA) and low voltage-activated (LVA) subtypes [1]. HVA channels activate at relatively depolarized potentials and comprise L-, P/Q-, N-, and R-types. LVA channels, known as T-type, are critically important for regulating neuronal excitability, pacemaking and post-inhibitory rebound burst firing [2],[3]. It should not come as a surprise that T-type channel hyperactivity has been associated to human neurological disorders such as absence epilepsy and neuropathic pain [4],[5],[6],[7]
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