Preferred Label : Calmodulin Pathway;
NCIt related terms : Ca / Calmodulin-dependent Protein Kinase Activation;
Alternative definition : BIOCARTA: The calcium/calmodulin-dependent kinases (CaMKs) are involved in a large
number of cellular responses induced by hormones, neurotransmitters and other signaling.
Elevation of calcium functions as a major second messenger, where the intracellular
concentration of calcium can be maintained at extremely low levels and subsequently
increased following specific calcium-mobilizing stimuli. There are many buffers to
the calcium fluctuations including membrane pumps and calcium-binding proteins that
create discrete spatial control of its effectors and their targets. The current family
of multifunctional calcium/calmodulin (CaM)-dependent protein kinases (CaMKs) consists
of CaMKI, CaMKII and CaMKIV. These kinases translate and co-ordinate the calcium fluctuations
into the appropriate cellular responses via phosphorylation. These kinases are partially
regulated by the intracellular calcium receptor calmodulin (CaM), and have common
as well as unique features in their structure, regulation and activation. CaMKII,
CaMKI and CaMKIV, have an autoregulatory domain that restricts or inhibits enzymatic
activity in the absence of calcium/CaM. Calcium/CaM binding alone produces maximal
activity of CaMKII, whereas CaMKI and CaMKIV have an activation loop that requires
phosphorylation of a threonine residue by CaMK kinase (CaMKK) for maximal activity.
Two genes (alpha and beta) for CaMKK, which is also regulated by CaM, have been identified.
The highest expression of these isoforms occurs in the brain but the activity of the
CaMKs has been identified in most cell types. CaMKIV has a post-calmodulin autophosphorylation
step that is not observed in CaMKI. The CaMKII multimer can autophosphorylate either
the autoregulatory domain or the CaM-binding domain, producing diverse effects in
its regulation and sensitivity to Calcium/CaM. Autophosphorylation of CaMKII can produce
Calcium/CaM- independent activity (autonomous activity), without affecting its maximal
Calcium/CaM-stimulated activity. The CaMKII autophosphorylation involves a kinase
cascade of sorts, with each subunit of the multimeric enzyme acting as both kinase
and kinase kinase. Autophosphorylation establishes a 1000-fold increase in the affinity
for its activator Calcium/CaM (also known as CaM trapping); however, autophosphorylation
within the CaM-binding domain following CaM dissociation of activated/autophosphorylated
enzyme restricts or prevents CaM from rebinding (CaM capping). The mechanisms and
consequences of autophosphorylation are central to the CaMKII enzyme's complex regulatory
behavior enabling it to become differentially activated at different frequencies and
levels of calcium spikes. The target proteins for the CaMKs are very similar. An example
target of the CaMKs is the transcriptional activating protein CREB. The phosphorylation
states of CREB after CaMK phosphorylation differ by the additional phosphorylation
of CREB at serine 142 that functions as an additional inhibitory site. This difference
appears to be the result of adjacent amino acids. (This definition may be outdated
- see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_CaCaMPathway;
Origin ID : C39009;
UMLS CUI : C1516152;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
