Edmond 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.

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.

Another key event in the history of PKA occurred when Susan Taylor and Janusz Sowadski at the University of California San Diego solved the three dimensional structure of the catalytic subunit of the enzyme.

[12] In addition, there are two other isoforms of the catalytic subunit of PKA called Cβ and Cγ arising from different genes but have similar functions as Cα.

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.

Several mutations in PRKACA have been found in patients with Cushing's syndrome that result in an increase in the ability of PKA to broadly phosphorylate other proteins.

One mutation in the PRKACA gene that causes an amino acid substitution of leucine to arginine in position 206, was found in over 60% of patients with adrenocortical tumors.

The Cα gene has also been incriminated in a variety of cancers, including colon, renal, rectal, prostate, lung, breast, adrenal carcinomas and lymphomas.

Given the wealth of information on the three dimensional structures of DNAJ and PKA Cα there is some hope that new drugs can be developed to target this atypical and potentially tumorigenic fusion kinase.