CAMP-dependent protein kinase PKA

A putative regulatory cofactor has been identified for the renal brush border Na /H exchanger (resistant-type) [50]. Morell et al. [50] identified a 42-kDa protein that was distinct from the transporter itself and appeared to be involved in regulation by cAMP-dependent protein kinase (PKA). Evidence supporting this conclusion was ... 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

FIGURE 1 2-2 Schematic diagram of the phosphorylation sites on each of the four 60kDa subunits of tyrosine hydroxylase (TOHase). Serine residues at the N-terminus of each of the four subunits of TOHase can be phosphorylated by at least five protein kinases. (J), Calcium/calmodulin-dependent protein kinase II (CaM KII) phosphorylates serine residue 19 and to a lesser extent serine 40. (2), cAMP-dependent protein kinase (PKA) phosphorylates serine residue 40. (3), Calcium/phosphatidylserine-activated protein kinase (PKC) phosphorylates serine 40. (4), Extracellular receptor-activated protein kinase (ERK) phosphorylates serine 31. (5), A cdc-like protein kinase phosphorylates serine 8. Phosphorylation on either serine 19 or 40 increases the activity of TOHase. Serine 19 phosphorylation requires the presence of an activator protein , also known as 14-3-3 protein, for the expression of increased activity. Phosphorylation of serines 8 and 31 has little effect on catalytic activity. The model shown includes the activation of ERK by an ERK kinase. The ERK kinase is activated by phosphorylation by PKC. (With permission from reference [72].)... 

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

Phosphorylation sites for one or more kinases are present on virtually all of the subunits. Phosphorylation of the P subunits by cAMP-dependent protein kinase (PKA) and phosphorylation of p and ysubunits by protein kinase C and tyrosine kinase have been reported [2, 17]. Current studies are directed toward an understanding of the functional consequences of phosphorylation of... 

FIGURE 21-6 Schematic illustration of the overall structure and regulatory sites of eleven different phosphodiesterase subtypes. The catalytic domain of the phosphodiesterases are relatively conserved, and the preferred substrate(s) for each type is shown. The regulatory domains are more variable and contain the sites for binding of Ca2+/calmodulin (CaM) and cGMP, as well as GAF and PAS domains. The regulatory domains also contain sites of phosphorylation by cAMP-dependent protein kinase (PKA). 

The principal component of heterologous (agonist-independent) desensitization of GPCRs is the rapid phosphorylation catalyzed by PKC and cAMP-dependent protein kinase (PKA). In studies using primary cultures and recombinant systems, the role of kinase-mediated phosphorylation of intracellular serines or threonines for the desensitization of the mGluR has been investigated (92-101). 

Furthermore, as well as CaCM-induced phosphorylation, MLCK is also subject to control via a cAMP-dependent protein kinase, PKA. Phosphorylated MLCK binds CaCM only weakly, thus contraction is impaired. This explains the relaxation of smooth muscle when challenged with adrenaline (epinephrine), a hormone whose receptor is functionally linked with adenylyl cyclase (AC), the enzyme that generates cAMP from ATP. 

In recent years, work by Loomis and co-workers has raised the possibility that cAMP oscillations in D. discoideum may originate from an intracellular regulatory network rather than from the mixed positive and negative feedback exerted by extracellular cAMP [84, 85]. These authors obtained evidence for an intracellular feedback loop involving MAP kinase and the cAMP-dependent protein kinase, PKA. The later enzyme would inactivate adenylate cyclase after a cAMP pulse. Numerical simulations of a model based on this intracellular negative feedback loop confirm that it can produce sustained oscillations of cAMP. 

Non-receptor serine/threonine kinases and dual specificity kinases cAMP-dependent protein kinase (PKA) Phosphoinositol-3-kinase (PI-3K) Cyclin-dependent kinase (CDK) Mitogen-activated protein kinase (MAPK) MAPKK (ERK)... 

FIGURE 25. Key interactions in the active site of the cAMP-dependent protein kinase (PKA) the additional H2O hgands on both hexacoordinated ions have been omitted for clarity and the... 

FIGURE 12-15 Activation of cAMP-dependent protein kinase, PKA. 

Mutations in PKA Explain how mutations in the R or C subunit of cAMP-dependent protein kinase (PKA) might lead to (a) a constantly active PKA or (b) a constantly inactive PKA. 

SNAP-25, a protein of 208 amino acids, deviates from the typical SNARE structure in that it has two SNARE motifs, joined by a flexible linker region, but lacks a transmembrane domain (Figure 1). The linker contains a cluster of four palmitoylated cysteine residues by which the protein is anchored at the plasma membrane. SNAP-25 can be phosphorylated at positions Thrl38 and Seri 87 by cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), respectively. SNAP-25 represents a small subgroup of SNAREs with a similar structure, including SNAP-23, SNAP-29, and SNAP-47. In contrast to the neuron-specific SNAP-25 these SNAREs are ubiquitously expressed. 

As discussed above, two of the established effectors of the Ga limb of heterotrimeric G-proteins are adenylate cyclase (AC) and phospholipase C (PLCP), which, on stimulation, lead to the generation of the second-messenger molecules, cAMP and DAG/IP3, respectively. Through the respective activation of cAMP-dependent protein kinase (PKA) and Ca2+/phospholipid-dependent protein kinase (PKC), GPCRs coupled to AC and PLCp have the potential to effect indirect modulation of neurotransmitter release by phosphorylation of substrate proteins involved in the... 

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