Modulation of the hyperpolarisation-activated current, Ih, in rat facial motoneurones in vitro by ZD-7288.
ZD-7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride] and Cs(+) have been used to distinguish the currents contributing to inward rectification in neonatal rat facial motoneurones (FMs). ZD-7288 (0.1-10 microM) inhibited a current that reversed at -43.7+/-3.7 mV in artificial cerebrospinal fluid (ACSF) containing 3 mM K(+) (n=9), and displayed the time and voltage dependence of the hyperpolarisation-activated current, I(h). Depolarisation-activated transient (I(K(A))) and sustained outward currents were unaffected by ZD-7288. The IC(50) for block of I(h) by ZD-7288 was around 0.2 microM. Onset of inhibition was slow and no recovery was seen after washing in ZD-7288-free ACSF for up to 4 h. In the presence of ZD-7288, Ba(2+) and Rb(+) blocked an inwardly rectifying potassium (K(+)) current, confirming both the presence of I(K(IR)) and its insensitivity to ZD-7288. Cs(+) rapidly and reversibly blocked both I(h) and I(K(IR)). Inhibition of I(h) by ZD-7288 showed no use dependence, internally applied ZD-7288 also blocked I(h), and tail current analysis indicated inhibition to be voltage-independent. In the presence of internal guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) and after previous exposure to ZD-7288, 5-hydroxytryptamine (5-HT), but not noradrenaline, promoted a recovery of I(h) that was not observed if ZD-7288 was present throughout the recording period. This interaction between ZD-7288 and irreversible 5-HT-receptor activation may be related to the mechanism underlying ZD-7288-mediated block of these channels.
Larkman
P M
PM
Department of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, Scotland, UK. p.larkman@ed.ac.uk
Kelly
J S
JS
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D005152:Facial Muscles / Q000187:drug effects / Q000502:physiology; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology
D002316:Cardiotonic Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D011743:Pyrimidines; D011985:Receptors, Serotonin; C082246:ICI D2788; D016244:Guanosine 5'-O-(3-Thiotriphosphate)