Mission CaMKIIγ: shuttle calmodulin from membrane to nucleus

Abstract

Neuronal plasticity depends on plasma membrane Ca(2+) influx, resulting in activity-dependent gene transcription. Calmodulin (CaM) activated by Ca(2+) initiates the nuclear events, but how CaM makes its way to the nucleus has remained elusive. Ma et al. now show that CaMKIIγ transports CaM from cell surface Ca(2+) channels to the nucleus.

Figure 1.. Excitation-Transcription Coupling by Ca²⁺/CaM-CaMKIIγ Shuttling

In hippocampal neurons (left), the depolarization-triggered Ca²⁺ influx via prevalent Ca_v1.2 leads to dephosphorylation and thereby activation of NFAT by AKAP5-anchored calcineurin, which is activated by Ca²⁺/CaM (Murphy et al., 2014). In SCG neurons, which are thought to lack Ca_v1.2, Ca²⁺ influx via Ca_v1.3 first results in clustering of Ca²⁺/CaM-CaMKIIγ and CaMKIIβ at or near clusters of Ca_v1.3 and calcineurin, which is probably linked to Ca_v1.3 by AKAP5 analogous to Ca_v1.2. The IQ motif (red segment) of Ca_v1.2 and Ca_v1.3 constitute docking sites for CaMKIIα and β, but not CaMKIIγ (Hudmon et al., 2005). The insert shows specific binding of increasing amounts of CaMKIIα to the IQ peptide TVGKFYATFLIQEYFR (red), but not to peptides upstream and downstream of IQ, in Ca_v1.2/Ca_v1.3 by fluorescence anisotropy assays (Z.A.M. and J.W.H., unpublished data), as seen earlier (Hudmon et al., 2005) (Kd here is 31 ± 7 nM). CaMKIIγ could bind to the Ca²⁺channel β subunit or Ca_v1.3-associated densin-180 (not depicted) (Hell, 2014). Effective delivery of Ca²⁺/CaM to the nucleus occurs upon phosphorylation of CaMKIIγT287 by CaMKIIβ for trapping of Ca²⁺/CaM and dephosphorylation of CaMKIIγS334 by calcineurin for nuclear import. Dephosphorylation of pT287 in CaMKIIγ by PP2A in the nucleus releases Ca²⁺/CaM for stimulation of CaMKK and CaMKIV. CaMKIV requires both Ca²⁺/CaM binding and phosphorylation of T196 by CaMKII before it can phosphorylate CREB on S133.