Trends in Pharmacological Sciences
OpinionProtein kinases: tuners of the BKCa channel in smooth muscle
Section snippets
PKA
The first protein kinase shown to affect the activity of smooth muscle BKCa channels was PKA (Fig. 1a) and several studies have confirmed this effect (Table 1). An alteration of BKCa channel activity was observed with either PKA concentrations between 10 and 500 nm or PKA activities between 0.01 and 50.00 U ml−1 (activities between 5 and 20 U ml−1 have been used most often). The EC50 for the PKA-induced activation of porcine tracheal BKCa channels is 0.12 U ml−1 (Ref. 17). By contrast, neither
Phosphorylation modulates BKCa channel activity
Although indirect mechanisms have been proposed 18, it is likely that the effects of protein kinases on BKCa channels involve direct phosphorylation of the channel protein. Several lines of evidence support this hypothesis.
Direct and indirect activation of BKCa channels by protein kinases
Another important issue is how protein kinases interact with the BKCa channel. There are two alternative hypotheses. The first suggests that protein kinases interact directly with the channel protein, whereas the second suggests that protein kinases interact with the channel indirectly, via other protein(s). It should be emphasized that this discussion is limited to data obtained from isolated BKCa channels, where factors that are known to affect BKCa channel function in intact cells, such as Ca
Concluding remarks
The activity of smooth muscle BKCa channels is regulated by protein kinases (Fig. 4). In most cases PKA and PKG stimulate and PKC inhibits channel activity by shifting the voltage–activation curve without changing single-channel conductance or voltage-sensitivity. This effect occurs following phosphorylation, which could be either direct at the channel, or indirect via a phosphatase. Questions regarding the interaction of different kinases at the BKCa channel, the effect of the kinases on
Chemical name
KT5823 (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-Kl]pyrrolo[3,4-i][1,6]benzo-diazocine-10-carboxylic acid, methyl ester
Acknowledgements
This work was supported by grants from Deutsche Forschungsgemeinschaft and the NIH. We would like to thank A. Bonev, T. Heppner and G. Perez for critical reading of the manuscript.
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