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PKA Isoforms

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PKA Isoforms Background

About PKA Isoforms

The protein kinase (PK) gene family is one of the largest in the human genome, comprising over 500 different PK-encoding genes. PKs catalyze the transfer of phosphate groups onto Ser, Thr, or Tyr residues of target proteins. Phosphorylation of substrates represents a key regulatory mechanism in all eukaryotic cells, and the various PKs target different substrates with a multitude of biological effects. The 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA) pathway is one of the most versatile and best-studied signaling pathways in eukaryotic cells.

Mammalian PKA is a tetramer composed of two catalytic (C) subunits, which phosphorylate specific serine and threonine residues on target substrates, and two regulatory (R) subunits, which bind cAMP and thus regulate catalytic activity. The two paralogous PKA catalytic subunits Cα and Cβ, encoded by the genes PRKACA and PRKACB, respectively, are among the best-understood model kinases in signal transduction research. Five different established or putative C subunit encoding genes have been identified in the human genome, PRKACA, PRKACB, PRKX, PRKY, and PRKACG.

Two major types of mammalian PKA, type I and type II (PKA I and PKA II), were initially described by their pattern of elution from DEAE-cellulose columns. These kinases were distinguished by the presence of different R subunits, termed RI and RII. Through biochemical studies and gene cloning, three isoforms of the C subunit, Cα, Cβ, and Cγ, and four isoforms of the R subunits, RIα, RIβ, RIIα, and RIIβ, have now been identified. In addition to different biochemical and functional properties, several lines of evidence support specific roles for the different PKA isoforms. RIα, RIIα, and Cα represent the ubiquitous mRNA forms found in most tissues, whereas mRNA for RIIβ seems to be cell and tissue-specific in its distribution, and its expression is hormonally regulated in ovarian granulosa cells and testicular Sertoli cells.

The cAMP/PKA signaling pathway.Fig.1 The cAMP/PKA signaling pathway. (Zhao M, et al., 2021)

Mechanism of Action of PKA Isoforms

The four regulatory isoforms of PKA (RIα, RIβ, RIIα, and RIIβ) play different roles in cells by regulating the activity and specificity of the PKA signaling pathway.

RIα (Regulatory subunit Iα): RIα is an isoform of the PKA regulatory subunit, the expression of which is widely distributed in a variety of cell types. RIα usually binds to the C subunit to form an inactive PKA tetramer. The function of RIα is to regulate PKA signaling by inhibiting the catalytic activity of the C subunit. RIα dissociates the C subunit by binding to cAMP, which allows it to gain activity and phosphorylates downstream target proteins.

RIβ (Regulatory subunit Iβ): RIβ is another isoform of the PKA regulatory subunit, and similar to RIα, it also regulates PKA signaling by inhibiting the catalytic activity of the C subunit. RIβ is expressed in certain tissues and cell types and functions in specific physiological processes.

RIIα (Regulatory subunit IIα): RIIα is another isoform of the PKA regulatory subunit. RIIα binds to the C subunit to form an inactive PKA tetramer. RIIα is characterized by the presence of two cAMP-binding sites in its structure, which allows RIIα to have a higher affinity for cAMP, thus allowing it to function at low concentrations of cAMP. RIIα activates PKA by releasing the C subunit to activate PKA and regulate the phosphorylation of downstream target proteins.

RIIβ (Regulatory subunit IIβ): RIIβ is another isoform of the PKA regulatory subunit and, similar to RIIα, has two cAMP binding sites. RIIβ is expressed in certain tissues and cell types and functions in specific physiological processes.

Functions of PKA Isoforms

Different isoforms of PKA play different roles in cells by regulating the activity and specificity of the PKA signaling pathway.

  • PRKACA (protein kinase A catalytic subunit alpha, Cα)

Cell signaling: PRKACA regulates the activity of multiple signaling pathways (e.g. transcription factors, ion channels, enzymes) in cells by phosphorylating substrate proteins. It can affect cell metabolism, proliferation, apoptosis, cytoskeleton reorganization, and other processes.

Metabolic regulation: PRKACA is involved in the regulation of multiple metabolic pathways, including glucose metabolism, lipid metabolism, and protein synthesis. It regulates insulin secretion, hepatic glucose production, fatty acid oxidation, and other processes.

  • PRKACB (protein kinase A catalytic subunit beta, Cβ)

Cell proliferation and survival: PRKACB is involved in the regulation of cell proliferation and survival. It phosphorylates regulatory cell cycle regulatory factors, apoptosis-associated proteins, and other proteins that affect cell growth, proliferation, and survival.

Neurological function regulation: PRKACB plays an important role in the nervous system and is involved in the regulation of learning memory, synaptic plasticity, and neural development.

  • PRKAR1B (protein kinase A regulatory subunit Iβ, R1β)

PKA signaling: PRKAR1B is involved in regulating PKA signaling. It binds cAMP and releases the C subunit, which in turn affects the downstream phosphorylation process and regulates a variety of physiological functions in cells.

Cell proliferation and differentiation: PRKAR1B is involved in regulating cell proliferation and differentiation. It phosphorylates regulatory transcription factors, apoptosis-associated proteins, and other molecules that affect cell fate and differentiation status.

Available Resources for PKA Isoforms

These PKA isoforms are functionally diverse, and depending on their expression and regulation in specific cell types, they can regulate a wide range of physiological processes within the cell, including, but not limited to, metabolic regulation, cell signaling, cell proliferation and differentiation, and counteracting stress. Therefore, studies targeting PKA isoforms are crucial for understanding cell biology and mechanisms of disease development and also provide important clues for potential therapeutic targets. Creative BioMart offers a variety of PKA isoforms-related research products, such as recombinant proteins, cell and tissue lysates, and protein pre-coupled magnetic beads, as well as customizable services and other resources to support your research in the field of PKA isoforms or PKA signaling pathway. The following PKA isoforms are displayed, click to view all related molecules/targets and research reagents. For further information or to purchase products, please contact us. We are committed to providing the highest quality resources and support for your research to help you succeed.

References:

  1. Zhao M, Wang Z, Yang M, et al. The Roles of Orphan G Protein-Coupled Receptors in Autoimmune Diseases. Clin Rev Allergy Immunol. 2021;60(2):220-243.
  2. Brandon EP, Idzerda RL, McKnight GS. PKA isoforms, neural pathways, and behavior: making the connection. Curr Opin Neurobiol. 1997;7(3):397-403.
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