Chloride - The Underrated Ion in Nociceptors.

Bettina U Wilke,Michaela Kress,Michael G Leitner,Kai K Kummer

doi:10.3389/fnins.2020.00287

Abstract

In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na+-K+-2Cl– cotransporter 1 (NKCC1) and K+-Cl– cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweety-homolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.

Highlights

In the past, excitation of primary afferent neurons has been associated mainly with cation fluxes across the cell membrane, setting the neurons’ excitability, responsiveness to tissue damaging stimuli as well as action potential (AP) generation and propagation
The intracellular Cl− concentration of neurons is maintained by cell membrane transporters including Na+-K+-2Cl− cotransporter 1 (NKCC1), or K+-Cl− cotransporter 2 (KCC2), the latter becomes prominent in mature neurons (Payne et al, 2003; Ben-Ari et al, 2012; Kaila et al, 2014)
As a consequence of the high intracellular Cl− concentration mediated by the active accumulation of Cl− by NKCC1, for example GABA-evoked depolarizing currents are observed in primary afferents at resting membrane potential (Sung et al, 2000); likewise, activation of G protein-coupled receptors, e.g. by lysophosphatidic acid (LPA) and sphingosine-1phosphate (S1P), has been shown to activate excitatory chloride conductances (Ponsioen et al, 2009; Camprubi-Robles et al, 2013; Qi et al, 2018)

Summary

INTRODUCTION

Excitation of primary afferent neurons has been associated mainly with cation fluxes across the cell membrane, setting the neurons’ excitability, responsiveness to tissue damaging stimuli as well as action potential (AP) generation and propagation. As a consequence of the high intracellular Cl− concentration mediated by the active accumulation of Cl− by NKCC1, for example GABA-evoked depolarizing currents are observed in primary afferents at resting membrane potential (Sung et al, 2000); likewise, activation of G protein-coupled receptors, e.g. by lysophosphatidic acid (LPA) and sphingosine-1phosphate (S1P), has been shown to activate excitatory chloride conductances (Ponsioen et al, 2009; Camprubi-Robles et al, 2013; Qi et al, 2018). DRG neuron cultures, which to a certain extent represent an axotomy model per se, develop increased GABAA current densities with time in culture (Lee et al, 2012) Other pain models such as formalin or reserpine injections are associated with upregulated α5 mRNA and protein expression in DRGs and spinal cord, and peripheral or intrathecal administration of an α5 antagonist prevents and reverses mechanical hypersensitivity (Bravo-Hernandez et al, 2016; De la Luz-Cuellar et al, 2019). This suggests that GlyR in primary afferent neurons are predominantly involved in setting transmission efficacy at SDH synapses but are not involved in nociceptive transduction

Glycine Receptors

Findings

CLC Family of Chloride Channels and Transporters