Sodium channels implement a molecular leaky integrator that detects action potentials and regulates neuronal firing

Abstract

Voltage-gated sodium channels play a critical role in cellular excitability, amplifying small membrane depolarizations into action potentials. Interactions with auxiliary subunits and other factors modify the intrinsic kinetic mechanism to result in new molecular and cellular functionality. We show here that sodium channels can implement a molecular leaky integrator, where the input signal is the membrane potential and the output is the occupancy of a long-term inactivated state. Through this mechanism, sodium channels effectively measure the frequency of action potentials and convert it into Na+ current availability. In turn, the Na+ current can control neuronal firing frequency in a negative feedback loop. Consequently, neurons become less sensitive to changes in excitatory input and maintain a lower firing rate. We present these ideas in the context of rat serotonergic raphe neurons, which fire spontaneously at low frequency and provide critical neuromodulation to many autonomous and cognitive brain functions.

Fast inactivation of Na+current in rat adrenal chromaffin cells involves two independent inactivation pathways

“…An analysis of Nav current in dorsal raphe neurons supports a similar dual-pathway model (Milescu et al, 2010), although the molecular basis for the inactivation in dorsal raphe neurons has not been determined. An accumulation of Nav channels in slow recovery states in raphe neurons has been proposed to act as a molecular integrator that essentially reports AP frequency and regulates firing (Navarro et al, 2020). A strength of the results presented here is that the rat CC currents are likely to arise from a single category of Nav channel, localized exclusively on the spherical plasma membrane.…”

Nav1.3 and fibroblast growth factor homologous factor 14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells

“…An important pair of papers on Nav currents in dorsal raphe neurons (Milescu et al, 2010; Navarro et al, 2020), almost certainly involving some as yet unidentified FGF, provides some of the more useful comparative information to the results presented here. Interesting differences between the Nav currents in CCs and those in dorsal raphe are that, whereas in CCs, inactivated channels are about equally distributed between fast and slow recovery pathways during a single depolarizing step, in dorsal raphe neurons only about 20% of channels enter initially slow recovery pathways (Milescu et al, 2010; Navarro et al, 2020). At present, we lack sufficient quantitative information about the differential entry and rates of recovery among different cell types to draw any conclusions, but below we consider a few factors that will need to be considered in future work.…”

“…Long-term Nav inactivation described in other systems (Dover et al, 2010; Navarro et al, 2020) has been shown or proposed to involve inactivation mediated by intracellular fibroblast growth factor homologous factors (abbreviated either FGFs or FHFs) (Smallwood et al, 1996; Munoz-Sanjuan et al, 2000). This family of proteins consists of a family of four peptides (FGF11-FGF14, also known as FHF3, FHF1, FHF2, or FHF4, respectively) with splice variation at the N-terminus.…”

“…The measurement we have available is the initial fractions of channels in fast and slow recovery pathways following brief inactivation steps, which for both rat and mouse CCs is about 0.5 for each. As mentioned, this does not appear to be case for raphe neurons (Navarro et al, 2020). For most other experimental work on FGFs to date, such quantitative information is not available.…”

“…The fast inactivation process leading to slow recovery is thought to occur in a largely competitive fashion with typical intrinsic fast inactivation. The slow recovery process provides a potential mechanism by which Nav channel availability may be reduced during repetitive activity, perhaps influencing the firing frequencies observed in CCs (Venkatesan et al, 2014; Navarro et al, 2020). In order to better understand the relationship between intrinsic fast inactivation and any competing fast inactivation process, it is important that the underlying molecular entities be defined.…”