PRKACA

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit (PKA Cα) is a member of the AGC kinase family (protein kinases A, G, and C), and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.2GU8, 3AGL, 3AGM, 3AMA, 3AMB, 3L9L, 3L9M, 3L9N, 3MVJ, 3NX8, 3OOG, 3OVV, 3OWP, 3OXT, 3P0M, 3POO, 3VQH, 4AE6, 4AE9, 4WB5, 4WB6, 4WB7, 4WB8, 5IZJ, 4UJB, 4UJA, 4UJ2, 4UJ1, 4UJ9556618747ENSG00000072062ENSMUSG00000005469P17612P05132NM_207518NM_001304349NM_002730NM_001277898NM_008854NP_001291278NP_002721NP_997401NP_001264827NP_032880Edmond H. Fischer and Edwin G. Krebs at the University of Washington discovered PKA in the late 1950s while working through the mechanisms that govern glycogen phosphorylase. They realized that a key metabolic enzyme called phosphorylase kinase was activated by another kinase that was dependent on the second messenger cyclic AMP (cAMP). They named this new enzyme the cAMP-dependent protein kinase, and proceeded to purify and characterize this new enzyme. Fischer and Krebs won the Nobel Prize in Physiology or Medicine in 1992 for this discovery and their continued work on kinases, and their counterparts the protein phosphatases. Today, this cAMP-dependent protein kinase is more simply noted as PKA.PRKACA is found on chromosome 19 in humans. There are two well-described transcripts of this gene, arising from alternative splicing events. The most common form, called Cα1, is expressed throughout human tissue. Another transcript, called Cα2, is found primarily in sperm cells and differs from Cα1 only in the first 15 amino acids.Inactive PKA holoenzyme exists as a tetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Biochemical studies demonstrated that there are two types of R subunits. The type I R subunits of which there are two isoforms (RIα, and RIβ) bind the catalytic subunits to create the type I PKA holoenzyme. Likewise type II R subunits, of which there are two isoforms (RIIα, and RIIβ), create the type II PKA holoenzyme. In the presence of cAMP, each R subunit binds 2 cAMP molecules and causes a conformational change in the R subunits that releases the C subunits to phosphorylate downstream substrates. The different R subunits differ in their sensitivity to cAMP, expression levels and subcellular locations. A-kinase-anchoring proteins (AKAPs) bind a surface formed between both R subunits and target the kinase to different locations in the cell. This optimizes where and when cellular communication occurs within the cell. Protein kinase A has been implicated in a number of diseases, including cardiovascular disease, tumors of the adrenal cortex, and cancer. It has been speculated that abnormally high levels of PKA phosphorylation contributes to heart disease. This affects excitation-contraction coupling, which is a rhythmic process that controls the contraction of cardiac muscle through the synchronized actions of calcium and cAMP responsive enzymes. There is also evidence to support that the mis-localization of PKA signaling contributes to cardiac arrhythmias, specifically Long QT syndrome. This results in irregular heartbeats that can cause sudden death.