Hyperforin modulates gating of P-type Ca2+ current in cerebellar Purkinje neurons.
Whole-cell, patch-clamp recordings from acutely isolated cerebellar Purkinje neurons demonstrate a two-stage modulation of P-type high-voltage-activated (HVA) Ca2+ current by a constituent of St. John's wort, hyperforin (0.04-0.8 microM). The first stage of modulation was voltage dependent and reversible. It comprised slow-down of the activation kinetics and a shift in the voltage dependence of P-current to more negative voltages. Hyperforin (0.8 microM) shifted the maximum of the current/voltage (I/V) relationship by -8+/-2 mV. The second, voltage-independent stage of modulation was manifested as a slowly developing inhibition of P-current that could not be reversed within the period of study. Neither form of modulation was abolished by intracellular guanosine 5'-O-(2-thiodiphosphate) (GDPPS) or guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) or by strong depolarising pre-pulses, indicating that modulation via guanine nucleotide-binding proteins (G proteins) is not involved in the observed phenomenon. Calmidazolium (0.5 microM), an antagonist of the intracellular Ca2+-binding protein calmodulin significantly inhibited the hyperforin-induced shift of the IIV curve maximum and the slow-down of the activation kinetics. It did not, however, affect the delayed inhibition of P-current, indicating that the two stages of modulation are mediated by separate mechanisms.
Fisunov
A
A
Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
Lozovaya
N
N
Tsintsadze
T
T
Chatterjee
S
S
Nöldner
M
M
Krishtal
O
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D020902:Hypericum; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010696:Phloroglucinol / Q000031:analogs & derivatives; D010946:Plants, Medicinal; D011689:Purkinje Cells / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000502:physiology; D013729:Terpenes / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D013729:Terpenes; D013873:Thionucleotides; D020867:omega-Agatoxin IVA; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C023427:guanosine 5'-O-(2-thiodiphosphate); D020866:omega-Conotoxin GVIA; D010696:Phloroglucinol; C001654:hyperforin