Quercetin metabolite 4-methylcatechol does not directly augment the activity of Kv7.4 or Kv7.5

Vascular smooth muscle voltage-gated potassium (Kv) channels, particularly
Kv7.4 and Kv7.5 homomers and/or heteromers, are increasingly being
recognized to play a role in regulating vascular smooth muscle cell
excitability. Thus, augmenting Kv7.4 and Kv7.5 activity to induce
vasorelaxation is being investigated as a mechanism for antihypertensive
drug development and the underlying molecular mechanism for the
antihypertensive effects of dietary components and traditional botanical
medicines. Recently, Dias and colleagues wrote that “Dietary polyphenols
have been associated with many beneficial cardiovascular effects. However,
these effects are rather attributed to small phenolic molecules
formed by the gut microbiota…4-Methylcatechol (4-MC) is one such
metabolite.” Dias and colleagues demonstrate that 4-MC (15 µM)
augments vasorelaxation induced by sodium nitroprusside or forskolin in
rat aortic rings. The vasorelaxation was inhibited by pan
voltage-gated potassium channel modulator 4-aminopyridine and to a lesser
extent by Kv7 inhibitor linopirdine, but not by soluble
guanylyl cyclase inhibitor ODQ. The authors concluded that “in
silico reverse docking confirmed that 4-MC binds to Kv7.4 through hydrogen
bonding and hydrophilic interactions” and “our findings
suggested that 4-MC exerts vasorelaxation by opening Kv channels
with the involvement of Kv7.4”. Here, we report that 4-MC has no direct
functional effect on Kv7.4 and Kv7.5 and may be weakly inhibitory to
Kv7.4/Kv7.5 heteromers at depolarized potentials. At 100 µM 4-MC has mild
augmenting effects at hyperpolarized potentials on the activity of Kv1.2,
Kv1.5, and Kv2.1, but not Kv1.1. In conclusion, it is critical that in
silico docking predictions be experimentally validated in order to
accurately draw conclusions about the identity of specific proteins as
pharmacological targets.