Multifunctional CaM kinase is activated by many neurotransmitters, hormones and growth factors that elevate intracellular free Ca2+. The kinase responds to these Ca2+-linked signal transaction systems by phosphorylating diverse substrates located in cytosolic, nuclear, cytoskeletal and membrane compartments. Its high concentration in brain, its implicated role in long-term potentiation and its regulation by autophosphorylation suggests that it may participate in neuronal plasticity and that it may function as a molecular memory device. Despite rapid advances in the field, however, many important biochemical and neuropharmacological issues remain unresolved, including: i) What is the mechanism of its biochemical memory -- how is the Ca2+- independent state of the kinase maintained in neurons? We will examine autophosphorylation that maintains its autonomous activity at basal Ca2+ and the autophosphorylation that desensitizes it to further stimulation. ii) Is the activity of CaM kinase and other calmodulin-dependent enzymes regulated by the availability of free calmodulin. We will test whether the limiting availability of calmodulin enables preferential activation of calcineurin over CaM kinase at low Ca2+. iii) What is the molecular basis for substrate specificity of CaM kinase isoforms and how do they differ from each other? We will determine the structural basis and functional consequence for the differential Ca2+/calmodulin sensitivity of a- and b-CaM kinase. iv) What are the functions of CaM kinase in brain? We will explore new strategies for inhibiting the kinase and examine its role in neurotransmitter release using mouse knockouts of CaM kinase and synapsin I.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Malmersjö, Seth; Di Palma, Serena; Diao, Jiajie et al. (2016) Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion. EMBO J 35:1810-21
Dey, Gautam; Jaimovich, Ariel; Collins, Sean R et al. (2015) Systematic Discovery of Human Gene Function and Principles of Modular Organization through Phylogenetic Profiling. Cell Rep :
Han, Kyuho; Jaimovich, Ariel; Dey, Gautam et al. (2014) Parallel measurement of dynamic changes in translation rates in single cells. Nat Methods 11:86-93
Malmersjö, Seth; Meyer, Tobias (2013) Inside-out connections: the ER meets the plasma membrane. Cell 153:1423-4
Bandara, Samuel; Malmersjö, Seth; Meyer, Tobias (2013) Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA. Sci Signal 6:ra56
Wollman, R; Meyer, T (2012) Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretion. Nat Cell Biol 14:1261-9
Liou, Jen; Fivaz, Marc; Inoue, Takanari et al. (2007) Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci U S A 104:9301-6
Tsui, Jennifer; Inagaki, Masaki; Schulman, Howard (2005) Calcium/calmodulin-dependent protein kinase II (CaMKII) localization acts in concert with substrate targeting to create spatial restriction for phosphorylation. J Biol Chem 280:9210-6
Schulman, Howard (2004) Activity-dependent regulation of calcium/calmodulin-dependent protein kinase II localization. J Neurosci 24:8399-403
Bradshaw, J Michael; Kubota, Yoshi; Meyer, Tobias et al. (2003) An ultrasensitive Ca2+/calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling. Proc Natl Acad Sci U S A 100:10512-7

Showing the most recent 10 out of 44 publications