Calmodulin (CaM) is an essential protein that serves as a ubiquitous intracellular receptor for Ca(2+). The Ca(2+)/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cellular functions. Among the many Ca(2+)/CaM-binding proteins to be discovered, the multifunctional protein kinases CaMKI, II, and IV play pivotal roles. Our review focuses on this class of CaM kinases to illustrate the structural and biochemical basis for Ca(2+)/CaM interaction with and regulation of its target enzymes. Gene transcription has been chosen as the functional endpoint to illustrate the recent advances in Ca(2+)/CaM-mediated signal transduction mechanisms.

Human Ca(2+)‐calmodulin (CaM) dependent protein kinase I (CaMKI) encodes a 370 amino acid protein with a calculated M(r) of 41,337. The 1.5 kb CaMKI mRNA is expressed in many different human tissues and is the product of a single gene located on human chromosome 3. CaMKI 1–306, was unable to bind Ca(2+)‐CaM and was completely inactive thereby defining an essential component of the CaM‐binding domain to residues C‐terminal to 306. CaMKI 1–294 did not bind CaM but was fully active in the absence of Ca(2+)‐CaM, indicating that residues 295–306 are sufficient to maintain CaMKI in an auto‐inhibited state. CaMKI was phosphorylated on Thr177 and its activity enhanced approximately 25‐fold by CaMKI kinase in a Ca(2+)‐CaM dependent manner. Replacement of Thr177 with Ala or Asp prevented both phosphorylation and activation by CaMKI kinase and the latter replacement also led to partial activation in the absence of CaMKI kinase. Whereas CaMKI 1–306 was unresponsive to CaMKI kinase, the 1–294 mutant was phosphorylated and activated by CaMKI kinase in both the presence and absence of Ca(2+)‐CaM although at a faster rate in its presence. These results indicate that the auto‐inhibitory domain in CaMKI gates, in a Ca(2+)‐CaM dependent fashion, accessibility of both substrates to the substrate binding cleft and CaMKI kinase to Thr177. Additionally, CaMKI kinase responds directly to Ca(2+)‐CaM with increased activity.