IndraLab

Statements



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"Sympathetic stimulation increases cAMP in SAMs, and binding of cAMP to HCN4 channels shifts pore opening to more depolarized membrane potentials and slows channel closing."

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"We studied the role of I (f) in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q)."

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"This depolarizing shift in voltage dependence appeared to result from direct binding of cAMP to HCN4 because it was eliminated by a point mutation (R669Q) at a conserved arginine in the CNBD that has been shown to disrupt cAMP binding to HCN4 and other cyclic nucleotide sensitive ion channels."

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"I (f) is produced by hyperpolarization activated cyclic nucleotide sensitive-4 (HCN4) channels, and it is widely believed that sympathetic regulation of I (f) occurs via direct binding of cAMP to HCN4, independent of phosphorylation."

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"While cAMP binding to HCN4 modulates I f activation (XREF_FIG), studies in which either HCN2 or HCN4 channel were genetically modified in mice, and prior studies in which I f current was blocked in numerous species by ionic or pharmacological maneuvers, do not indicate that I f is required for the SANC basal beating rate, or for its modulation by beta-AR stimulation."

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"Mice with a homozygous mutation of a single amino-acid exchange (R669Q) that prevented binding of cAMP to HCN4 channels, HCN4 R669Q and R669Q mice, are also embryonic lethal [XREF_BIBR]."

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"In contrast to knockout of RyR2, NCX or CaMKII function, or Ankyrin-B, or mutations in human RyRs, genetic manipulation in mice including HCN2 or HCN4 (general or cardiac specific SA node and AV node) knock outs, or inhibition of cAMP binding to HCN4 subunits, have minimal or no effects on resting heart rate, or on increases in heart rate during exercise, or chronotropic effect of beta-AR stimulation (XREF_SUPPLEMENTARY)."

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"The study by Xu et al. first examined steady-state binding of cAMP to an isolated HCN4 C-linker-CNBD fragment (called CL-CNBD) by using two different equilibrium binding assays, isothermal titration calorimetry and fluorescence anisotropy."

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"42 Similar observations were made in adult heterozygous knock-in mice expressing a cAMP binding deficient HCN4 subunit."