Regulation of neuronal cav3.1 channels by cyclin-dependent kinase 5 (Cdk5).

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.

• Authors: Aida Calderón-Rivera, Alejandro Sandoval, Ricardo González-Ramírez, Christian González-Billault, Ricardo Felix
• Journal: PloS one (PLoS One) Vol. 10 Issue 3 Pg. e0119134 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25760945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cacna1g protein, mouse
• Calcium Channels, T-Type
• Serine
• Cyclin-Dependent Kinase 5
• Cdk5 protein, mouse
• Calcium

Topics

• Animals
• Axons (physiology)
• Calcium (metabolism)
• Calcium Channels, T-Type (chemistry, genetics, metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Cell Movement
• Cyclin-Dependent Kinase 5 (genetics, metabolism)
• HEK293 Cells
• Humans
• Mice
• Mutagenesis, Site-Directed
• Neurons (cytology, physiology)
• Phosphorylation
• Serine (metabolism)