Norepinephrine selectively reduces slow Ca2+- and Na+-mediated K+ currents in cat neocortical neurons.
1. The effects of norepinephrine (NE) and related agonists and antagonists were examined on large neurons from layer V of cat sensorimotor cortex ("Betz cells") were examined in a brain slice preparation using intracellular recording, constant current stimulation and single microelectrode voltage clamp. 2. Application of NE (0.1-100 microM) usually caused a small depolarization from resting potential; hyperpolarizations were rare. Application of NE reversibly reduced rheobase and both the Ca2+- and Na+-dependent portions of the slow afterhyperpolarization (sAHP) that followed sustained firing evoked by constant current injection. The faster Ca2+-dependent medium afterhyperpolarization (mAHP), the fast afterhyperpolarization (fAHP), the action potential, and input resistance were unaffected. 3. The changes in excitability produced by NE application were most apparent during prolonged stimulation. The cells exhibited steady repetitive firing to currents that were formerly ineffective. The slow phase of spike frequency adaptation was reduced selectively and less habituation occurred during repeated long-lasting stimuli. The relation between firing rate and injected current became steeper if firing rate was averaged over several hundred milliseconds. 4. During voltage clamp in TTX, NE application selectively reduced the slow component of Ca2+-mediated K+ current. The faster Ca2+-mediated K+ current was unaffected, as were two voltage-dependent, transient K+ currents, the anomalous rectifier and leakage conductance measured at resting potential. Depolarizing voltage steps in the presence of Cd2+ revealed an apparent time- and voltage-dependent increase of the persistent Na+ current after NE application. The voltage-clamp results suggested ionic mechanisms for all effects seen during constant current stimulation except the depolarization from resting potential. The latter was insensitive to Cd2+ and TTX and occurred without a detectable change in membrane conductance. 5. NE application did not alter Ca2+ spikes evoked in the presence of TTX and 10 mM TEA. Inward Ca2+ currents examined during voltage clamp in TTX (with K+ currents reduced) became slightly larger after NE application. We conclude that NEs reduction of the slow Ca2+-mediated K+ current is not caused by reduction of Ca2+ influx. 6. Effects on membrane potential, rheobase, and the sAHP were mimicked by the beta-adrenergic agonist isoproterenol, but not by the alpha-adrenergic agonists clonidine or phenylephrine at higher concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Foehring
R C
RC
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle 98195.
Schwindt
P C
PC
Crill
W E
WE
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002415:Cats; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D004594:Electrophysiology; D007477:Ions; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D011188:Potassium / Q000502:physiology*; D011941:Receptors, Adrenergic / Q000502:physiology; D012964:Sodium / Q000502:physiology*; D013566:Sympathomimetics / Q000494:pharmacology
D007477:Ions; D011941:Receptors, Adrenergic; D013566:Sympathomimetics; D012964:Sodium; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine