Thalamocortical projections have a K+ channel that is phosphorylated and modulated by cAMP-dependent protein kinase

The single-channel recording technique was employed to investigate the mechanism conferring ATP sensitivity to a metabolite-sensitive K channel in insulin-secreting cells. ATP stimulated channel activity in the 0-10 microM range, but depressed it at higher concentrations. In inside-out patches, addition of the cAMP-dependent protein kinase inhibitor (PKI) reduced channel activity, suggesting that the stimulatory effect of ATP occurs via cAMP-dependent protein kinase-mediated phosphorylation. Raising ATP between 10 and 500 microM in the presence of exogenous PKI progressively reduced the channel activity; it is proposed that this inactivation results from a reduction in kinase activity owing to an ATP-dependent binding of PKI or a protein with similar inhibitory properties to the kinase. A model describing the effects of ATP was developed, incorporating these two separate roles for the nucleotide. Assuming that the efficacy of ATP in controlling the channel activity depends upon the relative concentrations of inhibitor and catalytic subunit associated with the membrane, our model predicts that the channel sensitivity to ATP will vary when the ratio of these two modulators is altered. Based upon this, it is shown that the apparent discrepancy existing between the sensitivity of the channel to low ATP concentrations in the excised patch and the elevated intracellular level of ATP may be explained by postulating a change in the inhibitor/kinase ratio from 1:1 to 3:2 owing to the loss of protein kinase after patch excision. At a low concentration of ATP (10-20 microM), a nonhydrolyzable ATP analogue, AMP-PNP, enhanced the channel activity when present below 10 microM, whereas the analogue blocked the channel activity at higher concentrations. It is postulated that AMP-PNP inhibits the formation of the kinase-inhibitor complex in the former case, and prevents phosphate transfer in the latter. A similar mechanism would explain the interaction between ATP and ADP which is characterized by enhanced activity at low ADP concentrations and blocking at higher concentrations.

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Cilostazol Suppresses Superoxide Production and Expression of Adhesion Molecules in Human Endothelial Cells via Mediation of cAMP-Dependent Protein Kinase-Mediated Maxi-K Channel Activation

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.098509 ◽

2006 ◽

Vol 317 (3) ◽

pp. 1238-1245 ◽

Cited By ~ 50

Author(s):

So Youn Park ◽

Jeong Hyun Lee ◽

Chi Dae Kim ◽

Won Suk Lee ◽

Won Sun Park ◽

...

Keyword(s):

Endothelial Cells ◽

Protein Kinase ◽

Adhesion Molecules ◽

Superoxide Production ◽

K Channel ◽

Human Endothelial Cells ◽

Dependent Protein Kinase ◽

Channel Activation ◽

Camp Dependent Protein Kinase ◽

Dependent Protein

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Role of cAMP-dependent protein kinase in cAMP-mediated vasodilation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.2.h511 ◽

1992 ◽

Vol 262 (2) ◽

pp. H511-H516 ◽

Cited By ~ 15

Author(s):

J. Haynes ◽

J. Robinson ◽

L. Saunders ◽

A. E. Taylor ◽

S. J. Strada

Keyword(s):

Protein Kinase ◽

Pressor Response ◽

Platelet Activating Factor ◽

K Channel ◽

Dependent Protein Kinase ◽

K Channels ◽

Pulmonary Vasodilation ◽

Camp Dependent Protein Kinase ◽

Dependent Protein

In this study, the role of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) in cAMP-dependent relaxation was assessed in the isolated-perfused rat lung using a PKA inhibitor, Rp-cAMPS, 8-bromo-cAMP (8-BrcAMP), and the diterpene activator of adenylate cyclase (AC), forskolin (FSK). A role for K+ channels was also assessed with the nonselective K+ channel blocker, tetraethylammonium (TEA, 10 mM), and an ATP-sensitive K+ channel inhibitor, glibenclamide (GLI, 100 microM). Both 8-BrcAMP (0.1-1.0 mM) and RSK (0.1-10 microM) dose-dependently attenuated the peak pressor response to alveolar hypoxia (HPR). Rp-cAMPS potentiated the HPR and attenuated 8-BrcAMP-mediated vasodilation but had no effect on FSK-mediated vasodilation. FSK-mediated vasodilation was not mimicked by 1,9-dideoxy-FSK, which is biologically inactive on AC but alters K+ channels identically to FSK, nor was it attenuated by the platelet-activating factor antagonist SRI 63-441 or the cyclooxygenase inhibitor indomethacin. TEA, but not GLI, attenuated FSK-mediated vasodilation. Similarly, TEA attenuated 8-BrcAMP-mediated vasodilation. These results support roles for PKA and indirect gating of a non-ATP-sensitive K+ channel in mediating cAMP-dependent pulmonary vasodilation.

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