Ether-à-go-go-related gene K+ channels contribute to threshold excitability of mouse auditory brainstem neurons.
The ionic basis of excitability requires identification and characterisation of expressed channels and their specific roles in native neurons. We have exploited principal neurons of the medial nucleus of the trapezoid body (MNTB) as a model system for examining voltage-gated K(+) channels, because of their known function and simple morphology. Here we show that channels of the ether-à-go-go-related gene family (ERG, Kv11; encoded by kcnh) complement Kv1 channels in regulating neuronal excitability around threshold voltages. Using whole-cell patch clamp from brainstem slices, the selective ERG antagonist E-4031 reduced action potential (AP) threshold and increased firing on depolarisation. In P12 mice, under voltage-clamp with elevated [K(+)](o) (20 mm), a slowly deactivating current was blocked by E-4031 or terfenadine (V(0.5,act) = -58.4 +/- 0.9 mV, V(0.5,inact) = -76.1 +/- 3.6 mV). Deactivation followed a double exponential time course (tau(slow) = 113.8 +/- 6.9 ms, tau(fast) = 33.2 +/- 3.8 ms at -110 mV, tau(fast) 46% peak amplitude). In P25 mice, deactivation was best fitted by a single exponential (tau(fast) = 46.8 +/- 5.8 ms at -110 mV). Quantitative RT-PCR showed that ERG1 and ERG3 were the predominant mRNAs and immunohistochemistry showed expression as somatic plasma membrane puncta on principal neurons. We conclude that ERG currents complement Kv1 currents in limiting AP firing at around threshold; ERG may have a particular role during periods of high activity when [K(+)](o) is elevated. These ERG currents suggest a potential link between auditory hyperexcitability and acoustic startle triggering of cardiac events in familial LQT2.
Hardman
Rachael M
RM
MRC Toxicology Unit, University of Leicester, Leicester, UK.
Forsythe
Ian D
ID
D000200:Action Potentials; D000818:Animals; D001306:Auditory Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008133:Long QT Syndrome / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012684:Sensory Thresholds
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C486376:KCNH7 protein, human; C000606915:Kcnh2 protein, mouse; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D012333:RNA, Messenger; C063968:E 4031; D011188:Potassium