RC3/Neurogranin and Ca2+/Calmodulin-dependent Protein Kinase II Produce Opposing Effects on the Affinity of Calmodulin for Calcium

Conserved properties of individual Ca 2+ -binding sites in calmodulin

“…Adding to the complexity, a single target may bind CaM with different conformations and stoichiometries that are Ca 2+ -dependent (67). Protein targets of CaM affect the apparent Ca 2+ affinity (68,69), and the protein complex is tuned to diverse physiological roles through evolution (70)(71)(72). How do the four EF-loops contribute to these diverse roles?…”

The Calmodulin Regulator Protein, PEP-19, Sensitizes ATP-induced Ca2+ Release

“…Ng knock-out mice show multiple effects on Ca 2ϩ dynamics, including increased base-line Ca 2ϩ levels and blunted Ca 2ϩ transients induced by synaptic activity or glutamate receptor agonists (36). We anticipate PEP-19 and Ng will influence distinct sets of Ca 2ϩ mobilization proteins and/or have different effects on the same proteins because PEP-19 increases both k on and k off of Ca 2ϩ binding to the C-domain (15), whereas Ng increases only Ca 2ϩ k off leading to decreased Ca 2ϩ binding affinity (37). Different cellular effects of PEP-19 and Ng are also suggested by different patterns of expression and because PEP-19 has anti-apoptotic effects (9, 10), whereas RC3 is reported to have pro-apoptotic activity (38,39).…”

IQ-Motif Proteins Influence Intracellular Free Ca2+in Hippocampal Neurons Through Their Interactions With Calmodulin

“…Experimental data shown were accomplished by rapidly mixing CaM (2 M) and Ca 2ϩ (100 M) with (black open circles) or without (black plus signs) 50 M of Ng, with 5 mM EGTA and the Tyr fluorescence signal from CaM was measured as an indication of Ca 2ϩ dissociation specifically from the C-terminal lobe. See Gaertner et al (2004) for more details. Results shown are from the ordinary differential equation (ODE) model using the parameter values listed in Table 1.…”

“…This corresponds to about 37-100 M of CaM (assuming the protein content is 0.25 g/ml cell volume as in Huang et al 2004). CaM binds four Ca 2ϩ ions: two Ca 2ϩ ions bind in a cooperative fashion to each lobe (Babu et al 1985;Gaertner et al 2004;Putkey et al 2003). Therefore CaM equips hippocampal neurons with about 148 -400 M of Ca 2ϩ -binding sites.…”

“…Neurogranin (Ng) is such a protein and its effect on the Ca 2ϩ -binding kinetics of CaM was recently identified (Gaertner 2004;Gaertner et al 2004;Putkey et al 2003). Neurogranin (Ng) and a related protein, PEP-19, are members of the IQ-motif family of CaM-binding proteins that interact with apo-CaM and Ca 2ϩ -CaM.…”