Characterization of the human HCN1 channel and its inhibition by capsazepine
| Autor: | Catherine H, Gill, Andrew, Randall, Stewart A, Bates, Kerstin, Hill, Davina, Owen, Phil M, Larkman, William, Cairns, Shahnaz P, Yusaf, Paul R, Murdock, Paul J L M, Strijbos, Andrew J, Powell, Christopher D, Benham, Ceri H, Davies |
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| Rok vydání: | 2004 |
| Předmět: |
Patch-Clamp Techniques
Potassium Channels Time Factors Dose-Response Relationship Drug Cyclic Nucleotide-Gated Cation Channels CHO Cells Benzazepines Transfection Electric Stimulation Ion Channels Cell Line Membrane Potentials Cricetulus Pyrimidines Cricetinae Papers Cyclic AMP Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Potassium Animals Humans Capsaicin |
| Zdroj: | British journal of pharmacology. 143(3) |
| ISSN: | 0007-1188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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