PKAR

Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signaling proteins, including PKA and PKG. PKA of phylogenetically distant Trypanosoma is the first exception as it is cyclic nucleotide-independent and responsive to nucleoside analogues (Bachmaier et al., 2019). Here, we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity CNB ligands and activators of PKA orthologs of the important tropical pathogens Trypanosoma brucei , Trypanosoma cruzi, and Leishmania ...

With unidentified chemical triggers and novel-effectors, cAMP signaling is broadly noncanonical in kinetoplastida parasites. Though novel protein kinase A regulatory subunits (PKAR) have been identified earlier, cAMP Response Proteins (CARPs) have been identified as a unique and definite cAMP effector of trypanosomatids. CARP1-CARP4 emerged as critical regulatory components of cAMP signaling pathway in Trypanosoma with evidences that CARP3 can directly interact with a flagellar adenylate cyclase (AC). CARP-mediated regulations, identified so far, reflects the mechanistic diversity of cAMP signaling...

Palatal mucosal changes secondary to smoking habit have been recognised since at least the 19th century. Smoker's palate, or nicotinic stomatitis is associated with habitual cigar or pipe smoking, regular consumption of thermally hot beverages and more recently has been identified in those who vape. It is considered of negligible malignant transformation risk, typically resolving on habit cessation. However a variant, palatal keratosis associated with reverse smoking (PKARs), is recognised as an established oral potentially malignant disorder...

Pulsatile insulin secretion by pancreatic beta cells is necessary for tight glucose control in the body. Glycolytic oscillations have been proposed as the mechanism for generating the electrical oscillations underlying pulsatile insulin secretion. The glycolytic enzyme 6-phosphofructokinase-1 (PFK) synthesizes fructose-1,6-bisphosphate (FBP) from fructose-6-phosphate (F6P). It has been proposed that the slow electrical and calcium oscillations (periods of 3-5 min) observed in islets result from allosteric feedback activation of PFKM by FBP...

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination...

Protein kinase A (PKA) is a widespread enzyme that plays a key role in many signaling pathways from lower eukaryotes to metazoans. In mammals, the regulatory (R) subunits sequester and target the catalytic (C) subunits to proper subcellular locations. This targeting is accomplished by the dimerization and docking (D/D) domain of the R subunits. The activation of the holoenzyme depends on the binding of the second messenger cAMP. The only available structures of the D/D domain proceed from mammalian sources...

Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+ , as found in blood plasma, leads to a rise in cytosolic Ca2+ , which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative phosphoproteomics, we found 394 protein phosphorylation site changes in merozoites subjected to different ionic environments (high K+ /low K+ ), 143 of which were Ca2+ dependent...

INTRODUCTION: ESD in the colon is an increasingly important technique in Western countries. There are few studies that include long term follow-up. AIM: to analyze the long term recurrence free survival rate after ESD and to compare recurrence rates according to different variables. METHODS: this was a prospective observational study of patients with a planned ESD from September 2008 to December 2015. When it was not possible to achieve an ESD, hybrid ESD was performed, either en bloc or piecemeal...

High fat diets are commonly used in aquaculture to reduce feed cost in Nile tilapia, but impair its lipid homeostasis. This study evaluated the role of forskolin on reducing fat accumulation in Nile tilapia (Oreochromis niloticus) by using in vitro and in vivo experiments. The use of 50 μM forskolin in vitro increased free fatty acid and glycerol release, but decreased triglyceride in adipocytes and hepatocytes. The adipose triglyceride lipase (ATGL), protein kinase cAMP-dependent type I regulatory subunit alpha (PKAR I) and other genes related to β-oxidation (peroxisome proliferator activated receptor alpha, PPARα and carnitine O-palmitoyltransferase 1, CPT1) were significantly up-regulated...

Aspergillus fumigatus mitogen-activated protein kinases (MAPKs) are involved in maintaining the normal morphology of the cell wall and providing resistance against cell wall-damaging agents. Upon cell wall stress, cell wall-related sugars need to be synthesized from carbohydrate storage compounds. Here we show that this process is dependent on cAMP-dependent protein kinase A (PKA) activity and regulated by the high-osmolarity glycerol response (HOG) MAPKs SakA and MpkC. These protein kinases are necessary for normal accumulation/degradation of trehalose and glycogen, and the lack of these genes reduces glucose uptake and glycogen synthesis...

BACKGROUND: The canonical heterotrimeric G protein-cAMP/PKA pathway regulates numerous cellular processes in filamentous fungi. Chaetomium globosum, a saprophytic fungus, is known for producing many secondary metabolites, including cytotoxic chaetoglobosin A (ChA), as well as abundant cellulase and xylanase. RESULTS: Here we report on the functional characterization of this signaling pathway in C. globosum. We blocked the pathway by knocking down the putative Gα-encoding gene gna1 (in the pG14 mutant)...

A pathogenic mutant, BCG183, was obtained by screening the T-DNA insertion library of Botrytis cinerea . A novel pathogenicity-related gene BcKMO , which encodes kynurenine 3-monooxygenase (KMO), was isolated and identified via thermal asymmetric interlaced PCR, bioinformatics analyses, and KMO activity measurement. The mutant BCG183 grew slowly, did not produce conidia and sclerotia, had slender hyphae, and presented enhanced pathogenicity. The phenotype and pathogenicity of the BcKMO -complementing mutant (BCG183/ BcKMO ) were similar to those of the wild-type (WT) strain...

Sensing the environmental signals, the canonical Gα-cAMP/PKA pathway modulates mycelial growth and development, and negatively regulates some secondary metabolism in filamentous fungi, e.g. aflatoxin in Aspergillus nidulans. Here we report the characterization of this signaling pathway in Chaetomium globosum, a widely spread fungus known for synthesizing abundant secondary metabolites, e.g. chaetoglobosin A (ChA). RNAi-mediated knockdown of a putative Gα-encoding gene gna-1, led to plural changes in phenotype, e...

Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1-3) and one regulatory (PKAr) subunits to integrate cAMP-dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down-regulation of PKAc1 or stabilisation of a dominant-negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis...

Prostaglandin E2 (PGE2 ), via cAMP signaling, inhibits a variety of fibroblast functions relevant to fibrogenesis. Among these are their translation of collagen I protein and their differentiation to myofibroblasts. PKA is central to these actions, with cAMP binding to regulatory (R) subunits leading to the release of catalytic subunits. Here we examined the role of specific PKAR subunit isoforms in these inhibitory actions in transforming growth factor β-1 (TGFβ-1)-stimulated human lung fibroblasts (HLFs)...

Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R-subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIα by enhancing the enzymatic activity...

Training subjects to step-in-place eyes open on a rotating platform while maintaining a fixed body orientation in space [podokinetic stimulation (PKS)] produces a posteffect consisting in inadvertent turning around while stepping-in-place eyes closed [podokinetic after-rotation (PKAR)]. Since the rationale for rehabilitation of curved walking in Parkinson's disease is not fully known, we tested the hypothesis that repeated PKS favors the production of curved walking in these patients, who are uneasy with turning, even when straight walking is little affected...

Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors...

OBJECTIVE: Turning around while stepping in place can be produced voluntarily. One way of producing involuntary turning around while stepping-in-place eyes closed is by training subjects onto a rotating platform while stepping-in-place and maintaining a fixed body orientation in space. This task produces a post-effect called "podokinetic after-rotation" (PKAR). Such training has been suggested for Parkinsonian patients. We tested the hypothesis that voluntary stepping-in-place and turning around also produces a post-effect similar to the PKAR...

Training subjects to step in place on a rotating platform while maintaining a fixed body orientation in space produces a posteffect consisting in inadvertent turning around while stepping in place eyes closed (podokinetic after-rotation, PKAR). We tested the hypothesis that voluntary turning around while stepping in place also produces a posteffect similar to PKAR. Sixteen subjects performed 12 min of voluntary turning while stepping around their vertical axis eyes closed and 12 min of stepping in place eyes open on the center of a platform rotating at 60°/s (pretests)...