Characterization of the human HCN1 channel and its inhibition by capsazepine

Br J Pharmacol. 2004 Oct;143(3):411-21. doi: 10.1038/sj.bjp.0705945. Epub 2004 Sep 6.


The human hyperpolarization-activated cyclic nucleotide-gated 1 (hHCN1) subunit was heterologously expressed in mammalian cell lines (CV-1 and CHO) and its properties investigated using whole-cell patch-clamp recordings. Activation of this recombinant channel, by membrane hyperpolarization, generated a slowly activating, noninactivating inward current. The pharmacological properties of hHCN1-mediated currents resembled those of native hyperpolarization-activated currents (I(h)), that is, blockade by Cs(+) (99% at 5 mm), ZD 7288 (98% at 100 microm) and zatebradine (92% at 10 microm). Inhibition of the hHCN1-mediated current by ZD 7288 was apparently independent of prior channel activation (i.e. non-use-dependent), whereas that induced by zatebradine was use-dependent. The VR1 receptor antagonist capsazepine inhibited hHCN1-mediated currents in a concentration-dependent (IC(50)=8 microm), reversible and apparently non-use-dependent manner. This inhibitory effect of capsazepine was voltage-independent and associated with a leftward shift in the hHCN1 activation curve as well as a dramatic slowing of the kinetics of current activation. Elevation of intracellular cAMP or extracellular K(+) significantly enhanced aspects of hHCN1 currents. However, these manipulations did not significantly affect the capsazepine-induced inhibition of hHCN1. The development of structural analogues of capsazepine may yield compounds that could selectively inhibit HCN channels and prove useful for the treatment of neurological disorders where a role for HCN channels has been described.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • CHO Cells
  • Capsaicin / analogs & derivatives*
  • Capsaicin / pharmacology*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / pharmacology
  • Cyclic Nucleotide-Gated Cation Channels
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / antagonists & inhibitors
  • Ion Channels / genetics
  • Ion Channels / physiology*
  • Membrane Potentials / drug effects
  • Patch-Clamp Techniques
  • Potassium / pharmacology
  • Potassium Channels
  • Pyrimidines / pharmacology
  • Time Factors
  • Transfection


  • Benzazepines
  • Cyclic Nucleotide-Gated Cation Channels
  • HCN1 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • Pyrimidines
  • ICI D2788
  • Cyclic AMP
  • capsazepine
  • Potassium
  • Capsaicin
  • zatebradine