A sodium background conductance controls the spiking pattern of mouse adrenal chromaffin cells in situ

Abstract

Key points Mouse chromaffin cells in acute adrenal slices exhibit two distinct spiking patterns, a repetitive mode and a bursting mode. A sodium background conductance operates at rest as demonstrated by the membrane hyperpolarization evoked by a low Na+‐containing extracellular saline. This sodium background current is insensitive to TTX, is not blocked by Cs+ ions and displays a linear I‐V relationship at potentials close to chromaffin cell resting potential. Its properties are reminiscent of those of the sodium leak channel NALCN. In the adrenal gland, Nalcn mRNA is selectively expressed in chromaffin cells. The study fosters our understanding of how the spiking pattern of chromaffin cells is regulated and adds a sodium background conductance to the list of players involved in the stimulus‐secretion coupling of the adrenomedullary tissue. Abstract Chromaffin cells (CCs) are the master neuroendocrine units for the secretory function of the adrenal medulla and a finely‐tuned regulation of their electrical activity is required for appropriate catecholamine secretion in response to the organismal demand. Here, we aim at deciphering how the spiking pattern of mouse CCs is regulated by the ion conductances operating near the resting membrane potential (RMP). At RMP, mouse CCs display a composite firing pattern, alternating between active periods composed of action potentials spiking with a regular or a bursting mode, and silent periods. RMP is sensitive to changes in extracellular sodium concentration, and a low Na+‐containing saline hyperpolarizes the membrane, regardless of the discharge pattern. This RMP drive reflects the contribution of a depolarizing conductance, which is (i) not blocked by tetrodotoxin or caesium, (ii) displays a linear I‐V relationship between −110 and −40 mV, and (iii) is carried by cations with a conductance sequence gNa > gK > gCs. These biophysical attributes, together with the expression of the sodium‐leak channel Nalcn transcript in CCs, state credible the contribution of NALCN. This inaugural report opens new research routes in the field of CC stimulus‐secretion coupling, and extends the inventory of tissues in which NALCN is expressed to neuroendocrine glands.

Basal and Stress-Induced Network Activity in the Adrenal Medulla In Vivo

“…The primacy of neuronal stimulation was also suggested in a study that recorded intracellular action potentials in freshly removed and bisected guinea pig adrenal glands ( 26 ) and in a study that detected catecholamine secretion using cyclic voltammetry and amperometry in rat adrenal slices ( 9 ). However, the conclusion seems to contradict studies in isolated chromaffin cells and in adrenal gland slices that detected non-neuronally evoked action potentials resulting from pacemaker activity ( 27 , 28 ). Indeed, a large body of work has documented an array of voltage-sensitive Ca 2+ channels and voltage and/or Ca 2+ -sensitive K + channels in chromaffin cells, some of which underlie the observed pacemaker activity (see reviews ( 22 , 29 ).…”

Fast inactivation of Nav1.3 channels by FGF14 proteins: An unconventional way to regulate the slow firing of adrenal chromaffin cells

“…The present findings on the recovery of Nav channels from inactivation allow for more precise interpretation of the recent reports on the different firing modes and secretory activity of rodent CCs summarized into two recent reviews ( Lingle et al, 2018 ; Carbone et al, 2019 ). There are, however, still open questions on how Nav availability may contribute to the transition of CCs from spontaneously firing to slow wave bursting ( Wallace et al, 2002 ; Martinez-Espinosa et al, 2014 ; Vandael et al, 2015 ; Guarina et al, 2017 ; Milman et al, 2021 ). As suggested by Martinez-Espinosa et al (2021b) , this might be solved using dynamic clamp experiments to evaluate the impact of conventional fast inactivation versus dual pathway fast inactivation on patterns of CC firing.…”

“…This point is also important for neuroendocrine cells, such as the spontaneously slow-firing chromaffin cells (CCs) of the adrenal medulla, which predominantly express TTX-sensitive neuronal Nav1.3 and Nav1.7 channels ( Lingle et al, 2018 ; Carbone et al, 2019 ). Rodent CCs undergo spontaneous or squared-pulse–evoked APs that, depending on Nav availability, will display spike trains (0.5–10 Hz) or bursts of APs ( Vandael et al, 2015 ; Guarina et al, 2017 ; Milman et al, 2021 ). Interestingly, the Nav channels of mouse CCs recover from fast inactivation with two exponential components with short and long time constants ( Vandael et al, 2015 ).…”

Exciting leak: Na+ background current makes chromaffin cells burst

“…Besides their classical roles in controlling cytosolic Ca 2+ concentration and therefore vesicle exo-and endocytosis, high voltage-gated Ca 2+ channels have been proposed to occupy the central role in setting the CCs' spontaneous and evoked electrical activity (Vandael et al 2010). A very elegant and thorough biophysical study coming from Nathalie Guerineau's laboratory, published in this issue of The Journal of Physiology, proposes a new molecular mechanism responsible for the dynamic switch between CCs' tonic and burst firing modes (Milman et al 2021). The authors characterize the CCs' spontaneous electrical activity in acute slices of mouse adrenal glands and, in accordance with previously published reports, they identify that ∼60% of the cells exhibit a spontaneous activity while the remaining cells are electrically quiet.…”

“…A very elegant and thorough biophysical study coming from Nathalie Guerineau's laboratory, published in this issue of The Journal of Physiology , proposes a new molecular mechanism responsible for the dynamic switch between CCs’ tonic and burst firing modes (Milman et al . 2021). The authors characterize the CCs’ spontaneous electrical activity in acute slices of mouse adrenal glands and, in accordance with previously published reports, they identify that ∼60% of the cells exhibit a spontaneous activity while the remaining cells are electrically quiet.…”