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@ARTICLE{Bidaud:153375,
      author       = {Bidaud, Isabelle and Chong, Antony Chung You and Carcouet,
                      Agnes and Waard, Stephan De and Charpentier, Flavien and
                      Ronjat, Michel and Waard, Michel De and Isbrandt, Dirk and
                      Wickman, Kevin and Vincent, Anne and Mangoni, Matteo E and
                      Mesirca, Pietro},
      title        = {{I}nhibition of {G} protein-gated {K}+ channels by
                      tertiapin-{Q} rescues sinus node dysfunction and
                      atrioventricular conduction in mouse models of primary
                      bradycardia.},
      journal      = {Scientific reports},
      volume       = {10},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DZNE-2020-01372},
      pages        = {9835},
      year         = {2020},
      abstract     = {Sinus node (SAN) dysfunction (SND) manifests as low heart
                      rate (HR) and is often accompanied by atrial tachycardia or
                      atrioventricular (AV) block. The only currently available
                      therapy for chronic SND is the implantation of an electronic
                      pacemaker. Because of the growing burden of SND in the
                      population, new pharmacological therapies of chronic SND and
                      heart block are desirable. We developed a collection of
                      genetically modified mouse strains recapitulating human
                      primary SND associated with different degrees of AV block.
                      These mice were generated with genetic ablation of L-type
                      Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both
                      (Cav1.3-/-/Cav3.1-/-). We also studied mice
                      haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and
                      mice in which the cAMP-dependent regulation of
                      hyperpolarization-activated f-(HCN4) channels has been
                      abolished (HCN4-CNBD). We analysed, by telemetric ECG
                      recording, whether pharmacological inhibition of the
                      G-protein-activated K+ current (IKACh) by the peptide
                      tertiapin-Q could improve HR and AV conduction in these
                      mouse strains. Tertiapin-Q significantly improved the HR of
                      Cav1.3-/- $(19\%),$ Cav1.3-/-/Cav3.1-/- $(23\%)$ and
                      HCN4-CNBD $(14\%)$ mice. Tertiapin-Q also improved cardiac
                      conduction of Nav1.5+/- mice by $24\%.$ Our data suggest
                      that the development of pharmacological IKACh inhibitors for
                      the management of SND and conduction disease is a viable
                      approach.},
      keywords     = {Animals / Bee Venoms: pharmacology / Bradycardia:
                      metabolism / Bradycardia: physiopathology / Calcium
                      Channels, L-Type: metabolism / Disease Models, Animal /
                      GTP-Binding Proteins: metabolism / Heart Conduction System:
                      drug effects / Heart Rate: drug effects / Mice / NAV1.5
                      Voltage-Gated Sodium Channel: metabolism / Potassium Channel
                      Blockers: pharmacology / Potassium Channels: metabolism /
                      Sinoatrial Node: drug effects / Sinoatrial Node:
                      physiopathology},
      cin          = {AG Isbrandt},
      ddc          = {600},
      cid          = {I:(DE-2719)1011003},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32555258},
      pmc          = {pmc:PMC7300035},
      doi          = {10.1038/s41598-020-66673-8},
      url          = {https://pub.dzne.de/record/153375},
}