Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons

Abstract

1. The role of multiple potassium conductances in action potential repolarization and repetitive firing behavior of hypoglossal motoneurons was investigated using intracellular recording techniques in a brain stem slice preparation of the neonatal rat (0-15 days old). 2. The action potential was followed by two distinct afterhyperpolarizations (AHPs). The early one was of short duration and is termed the fAHP; the later AHP was of longer duration and is termed the mAHP. The amplitudes of both AHPs were enhanced by membrane potential depolarization (further from EK). In addition, their amplitudes were reduced by high extracellular K+ concentration, suggesting that activation of potassium conductances underlies both phases of the AHP. 3. Prolongation of the action potential and blockade of the fAHP were observed after application of 1) tetraethylammonium (TEA) (1-10 mM) and 2) 4-aminopyridine (4-AP) (0.1-0.5 mM). Calcium channel blockers had little or no effect on the fAHP or action potential duration. 4. The size of the mAHP was diminished by 1) manganese, 2) lowering external Ca2+, 3) apamin, and 4) intracellular injection of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) suggesting that influx of calcium activates the potassium conductance that underlies the mAHP. 5. The mAHP was unaffected by nifedipine (20 microM), but was strongly reduced by focal application of omega-conotoxin GVIA, suggesting that N-type calcium channels represent the major calcium influx pathway for activation of the calcium-dependent K+ conductance underlying the mAHP. 6. Repetitive firing properties were investigated by injecting long-duration depolarizing current pulses. Steady-state firing rose linearly with injected current amplitude. The slope of the firing frequency-current (f-I) relationship averaged approximately 30 Hz/nA in control conditions. Blockade of the conductance underlying the mAHP caused a marked increase in the minimal repetitive firing frequency and in the slope of the f-I plot, indicating a prominent role for the conductance underlying the mAHP in controlling repetitive firing behavior. 7. We conclude that action potential repolarization and AHPs are due to activation of pharmacologically distinct potassium conductances. Whereas repolarization of the action potential and the fAHP involves primarily a voltage-dependent, calcium-independent potassium conductance that is TEA- and 4-AP-sensitive, the mAHP requires the influx of extracellular calcium and is apamin sensitive. Activation of the calcium-activated potassium conductance greatly influences the normal repetitive firing of neonatal hypoglossal motoneurons.

Beginning at the end: Repetitive firing properties in the final common pathway

“…This finding was supported by another modeling study (Kernell, 1968(Kernell, , 1972Kernell and Sjoholm, 1973). Although the focus continued to be on AHP conductance summation, subsequent investigators considered other processes, particularly in studies on brainstem motoneurons, where the AHP conductance was found to contribute to the early but not later phases of SFA (Sawczuk et al, 1997;Powers et al, 1999;Viana et al, 1993). Studies in neurons of the substantia gelatinosa (Melnick et al, 2004), dorsal root ganglion cells (Blair and Bean, 2003), neocortical neurons (Fleidervish et al, 1996), and hypoglossal motoneurons (Powers et al, 1999) demonstrated that SFA was not necessarily dependent on the AHP and led to the suggestion that the slow inactivation of sodium currents may be a contributing factor.…”

Control of Spontaneous Firing Patterns by the Selective Coupling of Calcium Currents to Calcium-Activated Potassium Currents in Striatal Cholinergic Interneurons

“…In several cell types, BK and SK potassium channels are coupled selectively to the various calcium channels (Viana et al, 1993;Sah, 1995;Williams et al, 1997;Marrion and Tavalin, 1998;Pineda et al, 1998;Cloues and Sather, 2003). Therefore, we sought to identify which calcium channels were responsible for the influx needed to activate the mAHP current.…”

“…In pyramidal cells, repolarization of action potentials, similar to cholinergic interneurons (Bennett et al, 2000), results from a potassium current through large-conductance calcium-activated potassium (BK) channels (Lancaster and Adams, 1986;Lancaster and Nicoll, 1987); mAHPs are generated by SK currents (Schwindt et al, 1988); and the calcium-dependent component of the sAHP that follows long trains of action potentials (Hotson and Prince, 1980;Gustafsson and Wigstrom, 1983;Schwindt et al, 1988) results from a potassium current that has yet to be identified (Sah and Faber, 2002;Vogalis et al, 2003). These calcium-dependent potassium currents rely on calcium entry through high-voltage-activated calcium channels (Viana et al, 1993;Sah, 1995;Williams et al, 1997;Pineda et al, 1998;Cloues and Sather, 2003). Several such cal-cium channels have been shown to contribute to barium currents recorded from dissociated cholinergic interneurons (Yan and Surmeier, 1996).…”

“…Several such cal-cium channels have been shown to contribute to barium currents recorded from dissociated cholinergic interneurons (Yan and Surmeier, 1996). One possible function for a diversity of calcium currents is the selective coupling of these channels to calciumdependent potassium channels (Viana et al, 1993;Sah, 1995;Williams et al, 1997;Marrion and Tavalin, 1998;Pineda et al, 1998;Shah and Haylett, 2000;Vilchis et al, 2000;Cloues and Sather, 2003). Because the calcium currents in cholinergic interneurons are targets of neuromodulation (Yan and Surmeier, 1996;Yan et al, 1997;Song et al, 2000;Pisani et al, 2002), finding such a selective coupling would provide a possible mechanism by which the firing patterns and the cholinergic output of these neurons are controlled by neuromodulators.…”

A ring of eight conserved negatively charged amino acids doubles the conductance of BK channels and prevents inward rectification

“…When open, the efflux of K ϩ out of the cell hyperpolarizes the membrane potential, turning off voltage-dependent Ca 2ϩ channels and reducing the influx of Ca 2ϩ available to both activate BK channels and control cellular processes. This negative feedback mechanism allows BK channels to play a key role in regulating many physiological processes, such as neurotransmitter release (10,11), repetitive firing of neurons (12), spike broadening during repetitive firing (13), the electrical tuning of hair cells in the cochlea (14,15), and muscle contraction (16).…”