Dopamine binds calmodulin during autoregulation of dopaminergic D2 receptor signaling through CaMKIIα-calmodulin complex

Abstract

The role of dopaminergic D2 receptor (D2R) autoregulation in dopamine (DA) neurotransmission cannot be overemphasized in cause and progression of disorders associated with complex behaviors. Although previous studies have shown that D2R is structurally and physiologically linked with calcium/calmodulin-dependent kinase II (CaMKIIα), however, the role of calmodulin in the CaMKIIα complex in D2R regulation remains elusive. In this study, using structural biology modeling softwares (iGEMDOCK and CueMol), we have shown the interaction between D2R, CaMKIIα, calmodulin, and DA under varying conditions. The outcomes of this study suggest that CaMKIIα causes a change in DA binding affinity to the D2R receptive site while the detached DA binds to calmodulin to stop the activity of D2R in the D2R–dopaminergic D1 receptor (D1R) heteromer. Ultimately, we concluded that D2R autoregulates to stop its heteromeric combination with D1R. D2R interacts with D1R to facilitate calcium movement that activates calmodulin, then CaMKIIα. The CaMKIIα-calmodulin complex changes the affinity of DA-D2R causing DA to break free and bind with calmodulin.

• Autoregulation
• calcium
• calmodulin
• CaMKIIα
• D2R
• dopamine

Acknowledgements

We will like to acknowledge the publishers of iGEMDOCK, CueMol, SPDB.exe for making these applications for free. Also we appreciate the authors and contributors on www.uniprot.org, www.rcsb.org, and www.drugbank.ca.

Declaration of interest

The authors hereby declare there is no conflict of interest associated with this study or any of the procedures and materials used for the purpose of the study. This work is supported by the ABUAD-DOR grant for the College of Medicine and Health Sciences, Afe Babalola University; awarded to O.O.M.