CAMP-protein kinase

Fig. 1.1 ATP bound to cAMP protein kinase and a schematic representation indicating the non-conserved regions (hydrophobic pocket and specificity surface) of the pocket utilised in the development of protein kinase inhibitors.

The mechanism of activation of protein kinases of type A by cAMP is schematically represented in Fig. 6.2. In the absence of cAMP, protein kinase A exists as a tetramer, composed of two regulatory (R) and two catalytic (C) subimits. In the tetrameric R2C2 form, protein kinase A is inactive since the catalytic center of the C subimit is blocked by the R subimit. 

Fig. 6.2. Regulation of protein kinase A via cAMP. Protein kinase A is a tetrameric enyzme composed of two catalytic subunits (C) and two regulatory subunits (R). In the R2C2 form, protein kinase A is inactive. Binding of cAMP to R leads to dissociation of the tetrameric enyzme into the R2 form with bound cAMP and free C subunits. In the free form, C is active and catalyzes the phosphorylation of substrate proteins (S) at Ser/Thr residues.

In addition to regulation by cAMP, protein kinase A is also subject to other regulatory influences. Thus, the C subunit may be specifically phosphorylated (see 7.2.1). It is not clear, however, which protein kinase is responsible for phosphorylation of the C suhunit. 

A protein kinase or protein phosphatase may be regulated by different signal transduction pathways. Thus, different external stimuli may influence the phosphorylation status of a protein. This differential stimulation may be mediated by the subunits of the enzyme, for example. For phosphorylase kinase, a Ca signal is registered by the Ca T calmodulin subunit whereas a cAMP protein kinase A signal is picked up in the form of a phosphorylation of the a and P subunits. Which of the signals comes into play depends on the current metabolic situation. 

The 1960s saw the emergence of the secondary messenger hypothesis (Rail et al., 1957). Binding the messenger to a regulatory protein could cause its dissociation and thus the unmasking of the active kinase (cAMP, protein kinase A), or on the... 

Artalejo CR, Ariano MA, Perlman RL, Fox AP (1990) Activation of facilitation calcium channels in chromaffin cells by D1 dopamine receptors through a cAMP/protein kinase A-dependent mechanism. Nature 348 239 12... 

Key Words Serotonin 5-HT receptor subtypes cAMP protein kinase A Gas. 

II is found on the surface of B cells, neutrophils, and macrophages and shows higher affinity for IL-1 p [7,59]. Types I and II are regulated differently in brain ischemia and may thus play separate roles. In spontaneously hypertensive rats, the mRNA for the type I IL-1 receptor was found to be relatively highly expressed in the normal cortex, with a marked increase 5 days after cerebral ischemia [7,58]. Type II mRNA has low basal expression and a peak 12 hours after the onset of ischemia [7,58]. The possible mechanisms of intracellular signal transduction for IL-1 on peripheral immune cells include effects on cAMP, protein kinase C, and protein phosphorylation. These effects remain to be proved in cerebral ischemia [7,59]. The IL-1-receptor interaction is quickly followed by the induction of immediate-early genes such as c-jun and c-fos [7,60]. 

England S, Bevan S, Docherty RJ 1996 PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat DRG neurones via the cAMP-protein kinase A cascade. J Physiol 495 429-440... 

Cannabinoids have been shown to induce cell cycle arrest in breast carcinoma (De Petrocellis et al. 1998), prostate carcinoma (Melck et al. 2000) and thyroid epithelioma cells (Bifulco et al. 2001). In breast carcinoma cells this has been ascribed to the inhibition of adenylyl cyclase and the cAMP/protein kinase A (PKA) pathway (Table 1). PKA phosphorylates and inhibits Raf-1, so cannabinoids prevent the inhibition of Raf-1 and induce prolonged activation of the Raf-l/MEK/ERK signalling cascade (Melck et al 1999). Cannabinoid-induced inhibition of thyroid epithelioma cell proliferation has been attributed to the induction of the cyclin-dependent kinase inhibitor p27 P (Portella et al. 2003). 

Melck D, Rueda D, Galve-Roperh I, De Petrocellis L, Guzman M, Di Marzo V (1999) Involvement of the cAMP/protein kinase pathway and of mitogen-activated protein kinase in... 

A unique representative of the CLC family is the epithelial CLC, GFTR, which is similar to the SUR subunit that regulates Kjj.6 of the Katp channel complexes. The GFTR is a unique CLC that transports CP across epithelial cells membranes and has ATPase activity that is used to drive the protein between open and closed conformations (Figure 16.18). To function, the CFTR requires phosporylation by cAMP-protein kinase (PKA). GFTR mutations lead to cystic fibrosis (Section 16.6). 

The molecular structure of the K a channel in smooth muscle is not known, although based on functional similarities, it would be expected to be a member of the mSlo family. K g channels seem to integrate many vasoactive signals that activate many important signal transduction pathways. The relative importance and regulation of Kca channels through cGMP-protein kinase, cAMP-protein kinase, or direct G-pro-tein activation pathways will be the subject of future research. 

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