CaMK I
CaMK I is a Ca2+/calmodulin-dependent kinase positioned downstream of CaMKK, linking intracellular calcium signals to cell-cycle control, neuronal polarity, osteoclast differentiation, and transporter trafficking[1][2][3][4]. Mechanistically, CaMKK activates CaMKI, CaMKIV, and AMPKα, and CaMKI activity supports Ca2+-dependent signaling programs in neuronal, metabolic, and pathophysiological pathways[5]. In hippocampal neurons, TRPC5-dependent localized calcium influx activated CaMKK and CaMKIγ, and CaMKIγ, but not other CaMKI isoforms, promoted axon formation[2]. Compared with related isoforms, CaMKI regulates G1, whereas CaMKII regulates G2/M and the metaphase-anaphase transition, limiting direct extrapolation from CaMKII inhibitor studies to CaMKI biology[1]. In osteoclast models, CaMKI and CaMKIIγ were present during RANKL-induced differentiation, and KN-93 or KN-62 inhibited osteoclastogenesis, cathepsin K expression, ERK phosphorylation, CREB activity, and bone resorption[3]. For experimental applications, STO-609-derived TIM-063 directly inhibited CaMKK and suppressed ionomycin-induced phosphorylation of CaMKI, CaMKIV, and AMPKα in cells, supporting pathway-level interrogation rather than CaMKI-selective inhibition[5].
References:
- [1]. Skelding KA, et al. Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II. Cell Cycle. 2011 Feb 15;10(4):631-9. [Content Brief]
- [2]. Davare MA, et al. Transient receptor potential canonical 5 channels activate Ca2+/calmodulin kinase Igamma to promote axon formation in hippocampal neurons. J Neurosci. 2009 Aug 5;29(31):9794-808. [Content Brief]
- [3]. Ang ES, et al. Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL). J Cell Physiol. 2007 Sep;212(3):787-95.
- [4]. Sung U, et al. Ca2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca2+ calmodulin kinases. J Chem Neuroanat. 2017 Oct;83-84:19-35. [Content Brief]
- [5]. Ohtsuka S, et al. Development and Characterization of Novel Molecular Probes for Ca2+/Calmodulin-Dependent Protein Kinase Kinase, Derived from STO-609. Biochemistry. 2020 May 5;59(17):1701-1710. [Content Brief]
