Protein Kinase A

In cell biology, protein kinase A, refers to a family of enzymes whose activity is dependent on the level of cyclic AMP (cAMP) in the cell. PKA is also known as cAMP-dependent protein kinase ). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.

Activation
Each PKA is a holoenzyme that consists of two regulatory and two catalytic subunits. Under low levels of cAMP, the holoenzyme remains intact and is catalytically inactive. When the concentration of cAMP rises (e.g. activation of adenylate cyclases by G protein-coupled receptors coupled to Gs, inhibition of phosphodiesterases which degrade cAMP), cAMP binds to the two binding sites on the regulatory subunits, which then undergo a conformational change that releases the catalytic subunits.

Catalysis
The free catalytic subunits can then catalyse the transfer of ATP terminal phosphates to protein substrates at serine, or threonine residues. This phosphorylation usually results in a change in activity of the substrate. Since PKAs are present in a variety of cells and act on different substrates, PKA and cAMP regulation are involved in many different pathways.

The mechanisms of further effects may be divided into direct protein phosphorylation and protein synthesis:
 * In direct protein phosphorylation PKA directly either increases or decreases the activity of a protein.
 * In protein synthesis PKA first directly activates CREB, which binds the cAMP response element, altering the transcription and therefore the synthesis of the protein. This mechanism generally takes longer time (hours to days).

Inactivation
PKA is thus controlled by cAMP. Also, the catalytic subunit itself can be regulated by phosphorylation.

Downregulation of protein kinase A occurs by a feedback mechanism: one of the substrates that is activated by the kinase is a phosphodiesterase, which quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A.

Anchorage
The 2 regulatory subunits of protein kinase A is important for localizing the kinase inside the cell, with the aid of A-kinase anchoring protein (AKAP), AKAP binds both to the regulatory subunits and to either a component of cytoskeleton structure or a membrane of an organelle, anchoring the enzyme complex to a particular subcellular compartment.

The catalytic function of protein kinase A would sometimes couple with the AKAP, binding PKA together with phosphodiesterase to form a complex that functions as a signal module. For example, an AKAP locating near the nucleus of a heart muscle cell, would bind to both PKA and phosphodiesterase that hydrolyzes cAMP. As phosphodiesterase contributes to the steady low concentration of cAMP in unstimulated cells, as the cell is stimulated, PKA is then responsible for the activation of phosphodiesterase (adjacent to PKA) in order to lower the concentration of cAMP, in this condition, as PKA and phosphodiesterase has formed a complex, the proximity increase the efficiency of PKA's activity.

Function
PKA phosphorylates other proteins, altering their function. However, what proteins are available for phosphorylation depends on in what kind of cell the PKA activity is present, since protein composition varies from cell type to cell type. Thus, the effects of PKA varies with cell type:

In adipocytes, myocytes and hepatocytes
Epinephrine and glucagon affect the activity of protein kinase A by changing the levels of cAMP in a cell via the G-protein mechanism, using adenylate cyclase. Protein Kinase A acts to phosphorylate many enzymes important in metabolism. Protein kinase A phosphorylates Acetyl-CoA carboxylase and pyruvate dehydrogenase. Allosteric regulation of these enzymes in such a manner has an inhibitory effect. Insulin will increase the level of phosphorylation of these enzymes, which will divert acetyl-coA down the lipogenesis pathway. Glucagon has an antagonistic effect.

In nucleus accumbens neurons
PKA helps transfer/translate the dopamine signal into cells. It has been found (postmortem) to be elevated in the brains of smokers, in the nucleus accumbens, which mediates reward and motivation: a part of the brain acted on by "virtually all" recreational drugs; as well as "in the area of the midbrain that responds to dopamine, which acts as a 'reward chemical' in smokers and former smokers."