Evolutionary Paths of the cAMP-Dependent Protein Kinase (PKA) Catalytic Subunits

Søberg, Kristoffer; Jahnsen, Tore; Rognes, Torbjørn; Skålhegg, Bjørn Steen; Laerdahl, Jon K.

doi:10.1371/journal.pone.0060935

Cited by 47 publications

(56 citation statements)

References 87 publications

(94 reference statements)

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“…C. elegans KIN-1 and KIN-2 show high protein sequence homology with mammalian PKA catalytic (ϳ80%) and regulatory (ϳ60%) subunit proteins. Multiple alignment and phylogram analysis showed that the isoforms of vertebrate PKA subunits would be diverged from ancestral forms as suggested previously (40). Thus, it appears that C. elegans PKA genes may have preserved ancestral forms of PKA and may be representative of many PKA genes among eukaryotes.…”

Section: Pka Subunit Stoichiometrysupporting

confidence: 63%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RI␣ and RII␤ via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent serine/threonine kinase that mediates various cellular responses, including lipolysis. Since its discovery in the 1950s (1-4), the cAMP-PKA system has become one of the best understood signaling pathways in terms of biochemical properties. PKA is composed of catalytic subunits and cAMP-binding regulatory subunits (5). In the absence of cAMP stimulation, PKA forms an inactive tetramer composed of four subunits with two regulatory and two catalytic subunits. Upon nutritional deprivation or hormonal stimulation, activated adenylyl cyclase produces cAMP from ATP. Then, the regulatory subunit of PKA binds cAMP, causing a conformational change that decreases its affinity for catalytic subunits by ϳ10 4 -fold and leads to the release of active catalytic subunits to phosphorylate target proteins (6, 7).PKA has a wide range of substrates that regulate a number of physiological processes. To date, several hundred PKA target proteins have been identified, and yet new PKA substrates are continually being reported (8, 9). In mammalian adipocytes, numerous studies over the last 40 years have revealed that the cAMP-PKA axis forms a critical node in the regulation of lipolysis. For instance, major components of lipolytic pathways, including hormone-sensitive lipase (Hsl) 2 and perilipin 1 (Plin1), are direct targets of PKA (10, 11). Recently, adipose triglyceride lipase (Atgl) was also reported to be a target of PKA (12, 13). Upon receiving activation signals from molecules such as catecholamine and glucagon, activated PKA phosphorylates Plin1 and HSL to promote the recruitment of HSL to lipid droplets (14, 15). In addition, phosphorylated Plin1 releases comparative gene identification-58 (CGI-58; Abhd5), a coactivator of Atgl, to mediate lipolysis upon PKA activation (16 -20). On the contrary, insulin can activate phosphodiesterase 3B (Pde3b) and reduce cAMP levels (1...

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Section: Pka Subunit Stoichiometrysupporting

confidence: 63%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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“…They have the same length and share 93% sequence identity (Soberg et al ., 2013). To confirm the O‐GlcNAcylation of PKAcs, we overexpressed PKAcα (PKAcα1) or PKAcβ (PKAcβ1) tagged with HA at the N‐terminal in HEK‐293FT cells and immunoprecipitated them with monoclonal anti‐HA.…”

Section: Resultsmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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SummaryAlzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O‐(2‐acetamido‐2‐deoxy‐d‐glucopyranosylidenamino) N‐phenylcarbamate (PUGNAc), an inhibitor of N‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD.

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“…PKA-Cα expression was measured due to its highest expression in brain tissues (Soberg et al, 2013, Uhler et al, 1986. Therefore, two antibodies for PKA subunits were chosen in the present study: anti-PKA-Cα (1:1000; Santa Cruz, #SC-903) and anti-phosphor-PKA-C (Thr197) (1:1000; Cell Signalling, #5661).…”

Section: Western Blotsmentioning

confidence: 99%

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

et al. 2016

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The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.

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Evolutionary Paths of the cAMP-Dependent Protein Kinase (PKA) Catalytic Subunits

Cited by 47 publications

References 87 publications

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

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