Preferred Label : Protein Kinase A Activation Pathway;
NCIt related terms : Activation of cAMP-dependent protein kinase, PKA;
Alternative definition : BIOCARTA: G-protein coupled receptors (GPCRs) comprise one of the largest gene families
of signaling proteins. Residing in the plasma membrane with seven transmembrane domains,
GPCRs respond to extracellular stimuli that include catecholamine neurotransmitters,
neuropeptides, larger protein hormones, lipids, nucleotides and other biological molecules.
When a GPCR binds its extracellular ligand, it interacts with a G-protein to transduce
a signal across the membrane into the cellular interior. G-proteins are a heterotrimeric
complex containing a Ga subunit with GTPase activity, as well as b and g subunits.
Ga can exist in an active state and an inactive state. Ga in the off state has GDP
bound and does not activate downstream signaling molecules. When a GPCR is activated
by ligand, it stimulates Ga subunits to bind GTP instead of GDP and become active,
dissociating from the receptor and from the b/g subunits to activate downstream signaling
factors like the enzyme adenylyl cyclase that synthesizes cyclic-AMP (cAMP) from ATP.
Ga turns itself back off again with its intrinsic GTPase activity, hydrolyzing GTP
to GDP to become inactive. Activated G proteins interact with downstream signaling
factors to alter the production of second messenger signaling molecules like inositolphosphates,
calcium and cAMP. GPCRs that activate the Gi class of Ga subunits inhibit cAMP production
and GPCRs that activate the Gs class of Ga subunits activate cAMP production. cAMP
in turn activates the cAMP-dependent protein kinase, protein kinase A (PKA). PKA is
a tetramer composed of catalytic subunits and regulatory subunits that repress the
catalytic units when they are bound together. The regulatory subunits bind cAMP when
it is present and release the catalytic units, releasing their inhibition of the catalytic
subunits as well. The catalytic subunits of PKA when they are released and active
phosphorylate target substrate proteins on serine and threonine residues, altering
the activity of the modified protein and creating a cellular response to the extracellular
stimulus acting on the GPCR. The PKA activation pathway is an example of a signal
transduction cascade, in which tying several signaling events together amplifies the
original signal in the cell. For each GPCR molecule that is activated, many G-proteins
can be activated, and each active G protein can synthesize many cAMP molecules, continuing
the cascade to PKA and further downstream. One of the roles of PKA that was first
studied was the regulation of glycogen metabolism. When epinephrine binds to its receptor
in liver, it activates cAMP production and PKA activation. One substrate of PKA is
phosphorylase kinase, which is activated by phosphorylation and is part of the signaling
cascade that mobilizes glycogen into glucose to provide energy that fuels the response
to epinephrine. Another substrate of PKA is glycogen synthase, which is turned off
by PKA phosphorylation. PKA also participates in many other signaling pathways, integrating
the key signaling intermediary cAMP with a wide range of biological responses. (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_gsPathway;
Origin ID : C39099;
UMLS CUI : C1514552;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
