Tetraethylammonium (TEA) increases the inactivation time constant of the transient K+ current in suprachiasmatic nucleus neurons

Abstract

Identifying the mechanisms that drive suprachiasmatic nucleus (SCN) neurons to fire action potentials with a higher frequency during the day than during the night is an important goal of circadian neurobiology. Selective chemical tools with defined mechanisms of action on specific ion channels are required for successful completion of these studies. The transient K + current (I A ) plays an active role in neuronal action potential firing and may contribute to modulating the circadian firing frequency. Tetraethylammonium (TEA) is frequently used to inhibit delayed rectifier K + currents (I DR ) during electrophysiological recordings of I A . Depolarizing voltage-clamped hamster SCN neurons from a hyperpolarized holding potential activated both I A and I DR . Holding the membrane potential at depolarized values inactivated I A and only the I DR was activated during a voltage step. The identity of I A was confirmed by applying 4-aminopyridine (5 mM), which significantly inhibited I A . Reducing the TEA concentration from 40 mM to 1 mM significantly decreased the I A inactivation time constant (τ inact ) from 9.8 ± 3.0 ms to 4.9 ± 1.2 ms. The changes in I A τ inact were unlikely to be due to a surface charge effect. The I A amplitude was not affected by TEA at any concentration or membrane potential. The isosmotic replacement of NaCl with choline chloride had no effect in I A kinetics demonstrating that the TEA effects were not due to a reduction of extracellular NaCl. We conclude that TEA modulates, in a concentration dependent manner, τ inact but not I A amplitude in hamster SCN neurons. SectionNeurophysiology; Neuropharmacology and other forms of Intercellular Communication

Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior

“…In the suprachiasmatic nucleus (SCN), the hypothalamic structure that controls circadian rhythms in mammalian physiology and behavior ( Kalsbeek and Buijs, 2002 ; Colwell, 2011 ), I A has been shown to be expressed and to modulate neuronal firing properties ( Bouskila and Dudek, 1995 ; Alvado and Allen, 2008 ; Itri et al, 2010 ; Granados-Fuentes et al, 2012 ; Granados-Fuentes et al, 2015 ). Voltage-clamp recordings from SCN neurons in slices prepared from mice harboring targeted disruptions in Kcnd2 (Kv4.2) or Kcnd3 (Kv4.3) revealed a role for Kv4.2, but not Kv4.3, in the generation of I A ( Granados-Fuentes et al, 2012 ).…”

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

“…In some cells, I A channels are active at subthreshold membrane potentials, influencing cell input resistances and excitability Yuan et al, 2005). I A is readily detected in SCN neurons and has been suggested to function in the regulation of repetitive firing rates (Huang, 1993;Bouskila and Dudek, 1995;Alvado and Allen, 2008). Using mice harboring targeted disruptions in the genes encoding the voltage-gated K ϩ (Kv) channel poreforming (␣) subunits, Kcna4 (Kv1.4…”

Membrane Currents, Gene Expression, and Circadian Clocks

“…Thus, the FDR K þ current is necessary for the circadian modulation of electrical activity in SCN neurons and represents an important part of the ionic basis for the generation of rhythmic output. The subthreshold-operating A-type K þ current (I A ) is mainly involved in the regulation of neuronal excitability and the timing of action potential firing (Huang 1993;Bouskila and Dudek 1995;Alvado and Allen 2008;Itri et al 2010). The magnitude of the I A current shows a diurnal rhythm that peaks during the day in the dorsal region of the mouse SCN (Itri et al 2010).…”