The calcium-activated slow AHP: cutting through the Gordian knot

Abstract

The phenomenon known as the slow afterhyperpolarization (sAHP) was originally described more than 30 years ago in pyramidal cells as a slow, Ca2+-dependent afterpotential controlling spike frequency adaptation. Subsequent work showed that similar sAHPs were widely expressed in the brain and were mediated by a Ca2+-activated potassium current that was voltage-independent, insensitive to most potassium channel blockers, and strongly modulated by neurotransmitters. However, the molecular basis for this current has remained poorly understood. The sAHP was initially imagined to reflect the activation of a potassium channel directly gated by Ca2+ but recent studies have begun to question this idea. The sAHP is distinct from the Ca2+-dependent fast and medium AHPs in that it appears to sense cytoplasmic [Ca2+]i and recent evidence implicates proteins of the neuronal calcium sensor (NCS) family as diffusible cytoplasmic Ca2+ sensors for the sAHP. Translocation of Ca2+-bound sensor to the plasma membrane would then be an intermediate step between Ca2+ and the sAHP channels. Parallel studies strongly suggest that the sAHP current is carried by different potassium channel types depending on the cell type. Finally, the sAHP current is dependent on membrane PtdIns(4,5)P2 and Ca2+ appears to gate this current by increasing PtdIns(4,5)P2 levels. Because membrane PtdIns(4,5)P2 is essential for the activity of many potassium channels, these finding have led us to hypothesize that the sAHP reflects a transient Ca2+-induced increase in the local availability of PtdIns(4,5)P2 which then activates a variety of potassium channels. If this view is correct, the sAHP current would not represent a unitary ionic current but the embodiment of a generalized potassium channel gating mechanism. This model can potentially explain the cardinal features of the sAHP, including its cellular heterogeneity, slow kinetics, dependence on cytoplasmic [Ca2+], high temperature-dependence, and modulation.

Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine

“…AHPs reflect conductances activated during spiking. Three AHPs have been described in neocortical pyramidal neurons (Abel et al 2004;Andrade et al 2012;Foehring 1992, 1993;Schwindt et al 1988aSchwindt et al , 1988b. The fast AHP reflects repolarization mechanisms for the AP, as well as residual inward currents and electrotonic redistribution of charge (Schwindt et al 1988b).…”

“…The sAHP has Ca 2ϩ -and Na ϩ -dependent parts (Foehring et al 1989;Gulledge et al 2013;Schwindt et al 1988b), requires multiple APs to activate, and is insensitive to apamin. The initial Ca 2ϩ -sensitive portion of the sAHP lasts ϳ1-2 s and is mediated by unknown channels that are negatively modulated by transmitters that activate PKA (e.g., NE through ␤-receptors; Andrade et al 2012;Foehring et al 1989). representative traces for a layer 3 pyramidal neuron in response to a Ϫ50-pA hyperpolarizing current injection (used to determine input resistance, R in ) and a ϩ150-pA depolarizing current injection that elicited 3 action potentials (APs).…”

“…Thus apamin blocked a current consistent with I mAHP in both cell types, but this current was much larger in glt cells. Given the microdomain interaction between intracellular Ca 2ϩ and SK channels (Abel et al 2004;Andrade et al 2012;Fakler and Adelman 2008;Jones and Stuart 2013), it is likely that either Ca 2ϩ entry is greater, or there are more SK channels expressed in glt cells vs. etv1 cells.…”

Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus

“…In CA1 pyramidal neurons of the dorsal hippocampus, a region important for learning and memory (Moser et al, 1995;Buzsáki and Moser, 2013), one of the most consistent manifestations of aging is an increased magnitude of the Ca 2ϩ -dependent, K ϩ -mediated slow afterhyperpolarization (sAHP; Landfield and Pitler, 1984;Moyer et al, 1992;Disterhoft and Oh, 2006;Gant et al, 2006). The sAHP is generated by hyperpolarizing Ca 2ϩ -sensitive K ϩ channels that are activated by action potential-induced Ca 2ϩ influx and resulting Ca 2ϩ release from intracellular ryanodine receptors (RyRs; Madison and Nicoll, 1984;Sah and Bekkers, 1996;Lancaster et al, 2001;Andrade et al, 2012). The aging-related increases in the hippocampal sAHP and other Ca 2ϩ -mediated processes, which act to dampen neuronal excitability, have been found to correlate with impaired learning in several species (Disterhoft et al, 1996;Thibault and Landfield, 1996;Tombaugh et al, 2005;Luebke and Amatrudo, 2012), suggesting that the mechanisms underlying Ca 2ϩ dysregulation may be directly relevant to brain dysfunction with aging.…”

Effect of flunarizine on memory function by using step down passive avoidance test in albino rats

“…Increases in the amplitude and duration of sAHPs result in decreases in intrinsic neuronal excitability, which is associated with impairment in learning and memory. 30 Flunarizine is a non-selective voltage dependent calcium channel blocker. It blocks not only the resting state but, more preferentially, the inactivated state of both the Land T-type Ca2+ channels.…”