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Comment
. 2010 Jun 16;29(12):1943-5.
doi: 10.1038/emboj.2010.105.

CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion

Ivar S Stein  1 , Johannes W Hell
Affiliations
Comment

CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion

Ivar S Stein et al. EMBO J. .
No abstract available

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
The CaMKII–M4 interaction. (A) Binding of CaMKII (red dodecamer) binds to the IL2 (red segment) of M4 (blue). Similar to the T286 segment (top in sequence alignment), the CaMKII-binding segments of GluN2B (middle) and M4 (bottom) can associate with the T site. M2 IL2, which does not bind CaMKII, differs in only two positions from the core-binding region of M4 IL2 (shadowed area). Residues shown in red and blue above the alignment are part of the functionally defined T and S sites of CaMKII, respectively. The T and S sites are in immediate proximity to each other and interact with the residues in the autoinhibitory domain and in GluN2B that are marked by red and blue boxes, respectively (because M4 does not depend on I205 in CaMKII and A153 is not a conservative substitution for F98-interacting residues, I152 and A153 are framed with dashed lines). The red box in bold depicts (auto) phopshorylation sites. In the inactive state, the T-site binding segment of the kinase is associated with the T site fostering binding of the pseudosubstrate segment (PS) to the S site. Ca2+–CaM binds immediately downstream of PS and R297 (and, upon T286 phosphorylation, N294; solid and dashed orange line) within PS to displace PS from the S site and thereby T286 from the T site. T286 can then bind the S site of a neighbouring Ca2+–CaM-activated kinase subunit with M281 interacting with F98 in the neighbouring subunit (blue box). The corresponding residue in GluN2B (L1298) is critical for the GluN2B–CaMKII association, suggesting that constitutive CaMKII association requires initial binding of GluN2B to the S site (Merrill et al, 2005) (see also Bayer et al, 2006). (B) Inhibition of D1 signalling by CaMKII-stimulated M4 and hypothesized Ca2+ influx and negative feedback loops. Ca2+ influx induces binding of CaMKII to M4 (red arrow). The ensuing phosphorylation of M4 augments the inhibitory effect of M4 through Gi/o on AC, which is otherwise stimulated by D1 through Gs. We propose NMDARs and L-type channels as likely candidates for the Ca2+ influx that activates CaMKII.
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References

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