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@ARTICLE{Leypold:866048,
      author       = {Leypold, Tim and Bonus, Michele and Spiegelhalter, Felix
                      and Schwede, Frank and Schwabe, Tina and Gohlke, Holger and
                      Kusch, Jana},
      title        = {{N} 6 -modified c{AMP} derivatives that activate protein
                      kinase {A} also act as full agonists of murine {HCN}2
                      channels},
      journal      = {The journal of biological chemistry},
      volume       = {294},
      issn         = {1083-351X},
      address      = {Bethesda, Md.},
      publisher    = {Soc.72889},
      reportid     = {FZJ-2019-05294},
      pages        = {17978-17987},
      year         = {2019},
      abstract     = {cAMP 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.},
      cin          = {JSC / NIC / ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$ /
                      Energetic and structural characterization of the activation
                      processes of the human HCN2 ion channel $(hdd17_20180501)$ /
                      Disinhibition and inhibition of HCN2 channel function by
                      ligand binding to the cyclic nucleotide bin
                      $(hdd17_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$ /
                      $G:(DE-Juel1)hdd17_20180501$ / $G:(DE-Juel1)hdd17_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31615893},
      UT           = {WOS:000504206800023},
      doi          = {10.1074/jbc.RA119.010246},
      url          = {https://juser.fz-juelich.de/record/866048},
}