Abstract
Calmodulin (CaM) is an important signaling molecule that regulates a vast array of cellular functions by activating second messengers involved in cell function and plasticity. Low voltage-activated calcium channels of the Cav3 family have the important role of mediating low threshold calcium influx, but were not believed to interact with CaM. We find a constitutive association between CaM and the Cav3.1 channel at rest that is lost through an activity-dependent and Cav3.1 calcium-dependent CaM dissociation. Moreover, Cav3 calcium influx is sufficient to activate αCaMKII in the cytoplasm in a manner that depends on an intact Cav3.1 C-terminus needed to support the CaM interaction. Our findings thus establish that T-type channel calcium influx invokes a novel dynamic interaction between CaM and Cav3.1 channels to trigger a signaling cascade that leads to αCaMKII activation.
Highlights
Calcium channels mediate a wide range of cellular functions that involve activation of calcium-dependent enzymes that can shape neuronal output [1]
CaM is known to establish an association with high voltage-activated (HVA) calcium channels to provide feedback regulation of channel activity or downstream activation of CaM-dependent protein kinase II (CaMKII)
The current study is important in showing that the Cav3.1 calcium channel exhibits a novel calcium-dependent interaction with CaM that triggers CaM-dependent activation and phosphorylation of αCaMKII
Summary
Calcium channels mediate a wide range of cellular functions that involve activation of calcium-dependent enzymes that can shape neuronal output [1]. Members of the Cav calcium channel family are designed to regulate calcium entry in the subthreshold voltage range to control action potential generation [2,3,4] and transmitter release [5,6,7,8]. Calcium entry through HVA calcium channels can trigger a second messenger cascade by which CaM activates Ca2+/CaM-dependent protein kinase II (CaMKII) that can modify cell activity and long-term plasticity [15,16,17,18,19]. The Cav channel family is reported to lack CaM binding consensus motifs that would permit calcium-dependent interactions with CaM [20, 21] and there are no reports of Cav calcium influx triggering a signaling cascade for CaMKII activation.
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