Protein kinase A is a target for aging and the aging heart

Abstract

PKA is an important mediator of signal transduction downstream of G-protein-coupled receptors and plays a key role in the regulation of metabolism and triglyceride storage. It is a ubiquitous cellular kinase that phosphorylates serine and threonine residues in response to cAMP. PKA consists of two regulatory subunits, RI and RII, that are activated by cAMP to release two catalytic subunits, Calpha and Cbeta. We have shown that C57/BL6J male mice lacking the regulatory RIIbeta subunit have extended lifespan and are resistant to age-related conditions including cardiac decline. In addition to being protected from diet-induced pathologies, PKA Cbeta null mutant mice are protected from age-related problems such as weight gain and enlarged livers, as well as cardiac dysfunction and hypertrophy. Several possible mechanisms for the age sparing effects of PKA inhibition are discussed including A kinase anchoring protein signaling, alterations in the beta-adrenergic pathway, and activation of AMPK. Since PKA is a major metabolic regulator of gene signaling, the human gene homologs are potential pharmacological targets for age-related conditions including heart disease associated with declining cardiac performance.

Figure 1.

The PKA pathway. The PKA pathway is a nutrient sensing pathway. In mammals, nutrients are sensed by a G-protein (GEF) that activates an adenylyl cylase (AC). AC produces cAMP, which binds to the regulatory subunits (R) of the PKA holoenzyme, releasing the catalytic subunits (C), which are then free to enter the nucleus of the cell and activate gene transcription or to interact with other signaling proteins in the cell.

Figure 2.

Proposed mechanism for how the PKA Cβ deletion results in resistance to obesity, fatty liver, and heart disease. Activation of AMPK is known to affect different aspects of lipid metabolism, and to play a role in protein synthesis. PKA inhibits activity of AMPK, and we have shown that loss of Cβ results in decreased levels of ChREBP. Our model proposes that disruption of Cβ and concomitant increased AMPK activity leads to a decrease in fatty acid and protein synthesis and an increase in lipolysis and fatty acid oxidation in select tissues. Leptin sensitivity caused by disruption of Cβ may also play a role in the observed increase in AMPK activity in our mutants. A compensatory increase by Cα in the brain also results in an increase in overall energy expenditure.