PKA inhibitors

Initial medicinal chemistry attempts to improve PKB kinase inhibitory selective exploited a previously described PKA inhibitor (compound 25, Fig. 5 ... 

Activation of P-ARs by isoproterenol enhances the expression of COX-2 and iNOS in a human urothelial cell line (Harmon et al., 2005). Since activation of P-adrenoreceptors leads to an increase in cAMP and a subsequent PKA activation, the authors investigated whether the increase in these inflammatory markers was due to activation of this pathway. However, this increase is independent of PKA, since PKA inhibitors did not reduce the augmentation in COX-2 and iNOS expression. 

It is well know that /3-adrenoceptors couple to adenylate cyclases to activate a protein kinase A (PKA), but no direct evidence exists for the involvement of the /3-adrenoceptor-PKA signaling pathway in the affective component of pain. Thus, we examined the effect of intra-vBNST administration of a selective PKA inhibitor on isoproterenol- and pain-induced aversion. CPA induced by the intra-vBNST injection of isoproterenol was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. These data suggest that PKA activation within the vBNST via the enhancement of /3-adrenergic transmission is important for the negative affective component of pain (Fig. 3). 

B) This effect is a mediated by a reduction in the sAHP, which curtails repetitive firing in these cells. The serotonin-induced reduction in the sAHP is mediated by 5-HT4 receptors (see text). The 5-HT4 receptor-mediated reduction of /sAHP is suppressed by the selective PKA inhibitor (Rp)cAMPs. 

The necessity of PKA activation for successful preconditioning is demonstrated by the following (i) the beta-adrenergic receptor blocker alprenolol partially abolished ischemic preconditioning (Lochner et al. 1999) (ii) landiolol, a short-acting beta-blocker, blunted the infarct size limitation induced by ischemic preconditioning (Sanada et al. 2004) (iii) PKA inhibitors such as H89 (Sanada et al. 2004 Inserte et al. 2004) and Rp-cAMPs (Sanada et al. 2004) blunted ischemic and dibutyryl-cAMP-induced preconditioning. 

An ITH injection of [D-Ala2]deltorphin II produces an acute antinociceptive tolerance [128], Concomitant pretreatment with lower doses of the PKC inhibitor calphostin C markedly prevents the development of acute tolerance to the ITH-administered [D-Ala2]deltorphin II-induced antinociception. On the other hand, the PKA inhibitor KT5720, has no effect on the development of acute tolerance to [D-Ala2]deltorphin II antinociception [128], It is therefore likely that PKC, but not PKA, plays an important role in the process of homologous desensitization of the spinal delta opioid receptor-mediated antinociception. 

The presence of an interaction between PKC and PKA in modulating TTX-R currents was demonstrated by the finding that the PKC inhibitors, PKCi9 3g staurosporine, significantly attenuated the ability of forskolin to modulate TTX-R currents. In contrast, the PKA inhibitors WIPTIDE and Rp-cAMPs failed to affect the PDBu-mediated changes in increases in peak TTX-R current conductance, although the PDBu effects on kinetics were reduced (Gold et al 1998). 

In primary cerebellar cultures and acutely isolated cerebellar granule neurons, methanandamide has been demonstrated to enhance NMDA-evoked calcium release (Netzeband et al., 1999). This effect was due to activation of the CB, receptor. In a smdy using inhibitors of VDCC, a variety of compounds known to modulate intracellular calcium release, and PKC and PKA inhibitors, it was determined that the enhancement of NMDA-evoked calcium release was due to CB,-receptor activation of the phospholipase C pathway this led to the downstream release of calcium from intracellular stores. In this study, it was also noted that blockade of the phospholipase C pathway unmasked a CB,-mediated inhibition of the NMDA-evoked calcium release (Netzeband et al., 1999). This is consistent with the study reported by Hampson et al. (1998) in rat brain shces, referred to earlier. 

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