Protein Kinase A-Cyclic AMP Signaling Pathway: An In-depth Report

This report provides a comprehensive analysis of the Protein Kinase A (PKA) and Cyclic AMP (cAMP) interaction, a crucial signaling pathway in cellular processes. PKA, a holoenzyme complex with catalytic and regulatory subunits, is activated by cAMP, a second messenger generated by GPCR activation. The report details the mechanism of PKA activation, including cAMP binding to the regulatory subunit, conformational changes, and subsequent dissociation of the catalytic subunit, leading to the phosphorylation of various metabolic enzymes. The report also discusses the impact of this interaction on glycogen synthesis, lipid biosynthesis, and other signaling pathways, such as the inactivation of phospholipase C and activation of MAP kinases. The report highlights how manipulation of the PKA-cAMP interaction can affect cellular functions, such as filamentous growth in S. cerevisiae, underscoring its importance in regulating body metabolism and energy production. References to relevant research papers are also included.

Running head: PROTEIN KINASE A- CYCLIC AMP
PROTEIN KINASE A- CYCLIC AMP
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1PROTEIN KINASE A- CYCLIC AMP
Protein kinase A- Cyclic AMP
Cyclic AMP-dependent protein kinase (PKA) is the signalling molecule which is known
to play key role in cellular process. Protein kinase A is dependent on cyclic AMP for signal
transduction. PKA stimulate the signal transduction pathway by phosphorylating the proteins.
The ligand of the enzyme is Cyclic AMP, which is responsible for activation of PKA and thereby
the signal cascade.
PKA is a holoenzyme complex which is composed of four subunits, two catalytic (C)
and two regulatory (R) subunits. These subunits are joined by disulphide bond. PKA is generally
located at the cytoplasm or it may be associated with the different organelle or cellular structure
depending on the type of regulation of PKA (Del Rio, Nielsen and Taylor 2017). It is anchored
with the help of A kinase anchor protein (AKAPs) in specific location. Major stimulator of PKA
is cAMP which acts as a second messenger. It is generated in response of GPCR protein by
activation of Adenylate Cyclase (Autenrieth et al. 2016). Such response is triggered by hormone
like glucagon.
R subunit have two cyclic AMP binding sites, which is auto-inhibitory domain that tend
to mimic pseudo-substrate motif RRGA1 for catalytic subunit. The catalytic subunit have ATP
binding domain with active binding site. Each of the (C) subunit is bounded with the regulatory
subunit via vanderwal interaction. cAMP binds at the R subunit and the complex undergo
conformational changes which causes its dissociation from C subunit. The activated C subunit
phosphorylates various metabolic enzymes and affects its signalling pathways in cell. Recent
studies suggest that PKA can get activated by sub cellular activation without physical separation
of the subunits (Eichel and von Zastrow 2018).

2PROTEIN KINASE A- CYCLIC AMP
The known substrate for phosphorylation are ion channels as well as various
transcription factors (Moleschi 2015). Such interaction is important to regulate the metabolism of
body through cascade of signals. For example, the interaction is known to phosphorylate
glycogen synthase and phosphorylase kinase. Protein kinase A- Cyclic AMP causes inhibition of
glycogen synthesis and facilitate glycogen breakdown respectively. The activation of C subunit,
phosphorylates acetyl CoA carboxylase enzyme which then inhibits biosynthesis of lipids. PKA
is also known to regulate the other signalling pathway like on phosphorylation, phospholipase C
is inactivated and thus activates the MAP kinases for signalling in cell division (Sepa‐Kishi et al.
2018).
If such interaction does not occur, the whole metabolism of body and its regulation will
be affected. Glycolysis will be inhibited in muscle cell and more glycogen will be synthesized.
Therefore, the cell of the body will not be able to produce ATP. The metabolism of lipid will be
greatly impacted as more lipid will be synthesis and no substrate would be available to produce
energy for body functioning.
Yes, we can manipulate the interaction of PKA and cyclic AMP. It is known that cAMP
is needed for activation of PKA, the interaction is manipulated to study the independent role of
PKA. For example, by biochemical manipulation of the interaction, increases the activity of PKA
which resulted in filamentous growth of S. cerevisiae. (Kayikci and Magwene 2018).

3PROTEIN KINASE A- CYCLIC AMP
Reference
Autenrieth, K., Bendzunas, N.G., Bertinetti, D., Herberg, F.W. and Kennedy, E.J., 2016.
Defining A‐Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI
(PKA‐RI). Chembiochem, 17(8), pp.693-697.
Del Rio, J.C., Nielsen, C.R. and Taylor, S.S., 2017. The Regulatory Subunit Type Iα of Protein
Kinase A: A Study of Carney Complex and Acrodysostosis Mutations. The FASEB
Journal, 31(1_supplement), pp.765-15.
Eichel, K. and von Zastrow, M., 2018. Subcellular organization of GPCR signaling. Trends in
pharmacological sciences, 39(2), pp.200-208.
Kayikci, Ö. and Magwene, P.M., 2018. Divergent Roles for cAMP–PKA Signaling in the
Regulation of Filamentous Growth in Saccharomyces cerevisiae and Saccharomyces
bayanus. G3: Genes, Genomes, Genetics, 8(11), pp.3529-3538.
Moleschi, K., 2015. Dissecting the Determinants of cAMP Affinity in Protein Kinase A (Doctoral
dissertation).
Sepa‐Kishi, D.M., Katsnelson, G., Bikopoulos, G., Iqbal, A. and Ceddia, R.B., 2018. Cold
acclimation reduces hepatic protein Kinase B and AMP‐activated protein kinase phosphorylation
and increases gluconeogenesis in Rats. Physiological reports, 6(5).