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000866048 1001_ $$0P:(DE-HGF)0$$aLeypold, Tim$$b0
000866048 245__ $$aN 6 -modified cAMP derivatives that activate protein kinase A also act as full agonists of murine HCN2 channels
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000866048 520__ $$acAMP acts as a second messenger in many cellular processes. Three protein types mainly mediate cAMP-induced effects: PKA, exchange protein directly activated by cAMP (Epac), and cyclic nucleotide–modulated channels (cyclic nucleotide–gated or hyperpolarization-activated and cyclic nucleotide–modulated (HCN) channels). Discrimination among these cAMP signaling pathways requires specific targeting of only one protein. Previously, cAMP modifications at position N6 of the adenine ring (PKA) and position 2′-OH of the ribose (Epac) have been used to produce target-selective compounds. However, cyclic nucleotide–modulated ion channels were usually outside of the scope of these previous studies. These channels are widely distributed, so possible channel cross-activation by PKA- or Epac-selective agonists warrants serious consideration. Here we demonstrate the agonistic effects of three PKA-selective cAMP derivatives, N6-phenyladenosine-3′,5′-cyclic monophosphate (N6-Phe-cAMP), N6-benzyladenosine-3′,5′-cyclic monophosphate (N6-Bn-cAMP), and N6-benzoyl-adenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP), on murine HCN2 pacemaker channels. Electrophysiological characterization in Xenopus oocytes revealed that these derivatives differ in apparent affinities depending on the modification type but that their efficacy and effects on HCN2 activation kinetics are similar to those of cAMP. Docking experiments suggested a pivotal role of Arg-635 at the entrance of the binding pocket in HCN2, either causing stabilizing cation–π interactions with the aromatic ring in N6-Phe-cAMP or N6-Bn-cAMP or a steric clash with the aromatic ring in N6-Bnz-cAMP. A reduced apparent affinity of N6-Phe-cAMP toward the variants R635A and R635E strengthened that notion. We conclude that some PKA activators also effectively activate HCN2 channels. Hence, when studying PKA-mediated cAMP signaling with cAMP derivatives in a native environment, activation of HCN channels should be considered.
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000866048 536__ $$0G:(DE-Juel1)hdd17_20180501$$aEnergetic and structural characterization of the activation processes of the human HCN2 ion channel (hdd17_20180501)$$chdd17_20180501$$fEnergetic and structural characterization of the activation processes of the human HCN2 ion channel$$x2
000866048 536__ $$0G:(DE-Juel1)hdd17_20170501$$aDisinhibition and inhibition of HCN2 channel function by ligand binding to the cyclic nucleotide bin (hdd17_20170501)$$chdd17_20170501$$fDisinhibition and inhibition of HCN2 channel function by ligand binding to the cyclic nucleotide bin$$x3
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000866048 7001_ $$0P:(DE-HGF)0$$aBonus, Michele$$b1
000866048 7001_ $$0P:(DE-HGF)0$$aSpiegelhalter, Felix$$b2
000866048 7001_ $$0P:(DE-HGF)0$$aSchwede, Frank$$b3
000866048 7001_ $$0P:(DE-HGF)0$$aSchwabe, Tina$$b4
000866048 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b5
000866048 7001_ $$00000-0001-7206-8133$$aKusch, Jana$$b6$$eCorresponding author
000866048 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.RA119.010246$$gp. jbc.RA119.010246 -$$p17978-17987$$tThe journal of biological chemistry$$v294$$x1083-351X$$y2019
000866048 8564_ $$uhttps://juser.fz-juelich.de/record/866048/files/J.%20Biol.%20Chem.-2019-Leypold-17978-87-1.pdf$$yPublished on 2019-10-15. Available in OpenAccess from 2020-10-15.
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