Functional Insights into Protein Kinase A (PKA) Signaling from C. elegans

Abstract

Protein kinase A (PKA), which regulates a diverse set of biological functions downstream of cyclic AMP (cAMP), is a tetramer consisting of two catalytic subunits (PKA-C) and two regulatory subunits (PKA-R). When cAMP binds the PKA-R subunits, the PKA-C subunits are released and interact with downstream effectors. In Caenorhabditis elegans (C. elegans), PKA-C and PKA-R are encoded by kin-1 and kin-2, respectively. This review focuses on the contributions of work in C. elegans to our understanding of the many roles of PKA, including contractility and oocyte maturation in the reproductive system, lipid metabolism, physiology, mitochondrial function and lifespan, and a wide variety of behaviors. C. elegans provides a powerful genetic platform for understanding how this kinase can regulate an astounding variety of physiological responses.

Keywords: C. elegans; PKA; behavior; cAMP; calcium signaling; physiology.

Figure 1

Schematic representation of AKAP binding PKA. AKAP binds the regulatory subunit of PKA, regulating PKA’s subcellular localization and co-locating PKA with specific phosphorylation targets, such as proximal to the ER or plasma membrane. Created with BioRender.com (accessed on 31 October 2022).

Figure 2

Schematic representation of G-protein activation of PKA. PKA is activated when the regulatory subunit binds to cAMP, releasing the catalytic subunit. cAMP is produced by adenylyl cyclase, which is either activated by Gαs, or inhibited by Gαi/o. Adapted from “Activation of Protein Kinase A (PKA)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 27 October 2022).

Figure 3

Schematic representation of fasting-induced lipolysis model via the cAMP pathway. Food deprivation increases cAMP and activates PKA. PKA-C activates the adipose triglyceride lipase ATGL-1, which then forms a liquid droplet with lipid droplet protein LID-1, which leads to lipid hydrolysis. Adapted with permission from [86], 2022, American Society for Microbiology. Created with BioRender.com (accessed on 23 October 2022).

Figure 4

Schematic representation of proposed signaling pathway in B- and D- type motor neurons. G_αs GSA-1 activates adenylyl cyclase ACY-1, producing more cAMP and therefore activating PKA. TWK-7 is a K₂P channel that normally decreases locomotion. Through a mechanism that is not entirely understood (dotted line) active PKA inhibits TWK-7, therefore increasing locomotion. Adapted with permission from [99], 2022, Oxford University Press. Created with BioRender.com (accessed on 23 October 2022).

Figure 5

Schematic representation of axon regeneration model through JNK MAPK pathway by Ca²⁺ and cAMP signaling pathways. Adapted with permission from [115], 2022, Creative Commons. Created with BioRender.com (accessed on 23 October 2022).