Chloride – The Underrated Ion in Nociceptors

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, Ca 2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweetyhomolog 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.

Balance of Na+, K+, and Cl– Unidirectional Fluxes in Normal and Apoptotic U937 Cells Computed With All Main Types of Cotransporters

“…Later, the interplay between various cation-coupled Cl – cotransporters (SLC12 gene family) and Cl – channels has been intensively studied in relation to signal transduction in neurons ( Kaila et al, 2014 ; Doyon et al, 2016 ; Currin et al, 2020 ; Wilke et al, 2020 ), in astroglia physiology ( Wilson and Mongin, 2018 ) and in phagocytosis ( Wang, 2016 ; Perry et al, 2019 ). Unfortunately, in all these cases, it was extremely difficult to obtain a complete set of accurate and reliable experimental data necessary for quantitative description of the entire flux balance across the cell membrane.…”

“…The balance of Cl − fluxes through cotransporters and channels was not considered in the early fundamental studies of cotransporters in erythrocytes because the distribution of Cl − is determined in these cells by a powerful Cl − /HCO 3 − exchanger, but not by Cl − channels. Later, the interplay between various cation-coupled Cl − cotransporters (SLC12 gene family) and Cl − channels has been intensively studied in relation to signal transduction in neurons (Kaila et al, 2014;Doyon et al, 2016;Currin et al, 2020;Wilke et al, 2020), in astroglia physiology (Wilson and Mongin, 2018) and in phagocytosis (Wang, 2016;Perry et al, 2019). Unfortunately, in all these cases, it was extremely difficult to obtain a complete set of accurate and reliable experimental data necessary for quantitative description of the entire flux balance across the cell membrane.…”

“…This is what makes Cl − an active player in various physiological processes (Jentsch, 2016) since the permeability of the Cl − channels can affect the entire homeostasis of monovalent ions only when Cl − is in a non-equilibrium state. The interplay of various Cl − coupled cotransporters and Cl − channels has been particularly intensively studied in connection with signal transmission in neurons (Kaila et al, 2014;Doyon et al, 2016;Currin et al, 2020;Wilke et al, 2020). Progress in the molecular biology of the cation-coupled Cl − cotransporters is exciting; however, their functional expression and role in maintaining Cl − homeostasis in non-polarized cells is investigated much worse because electrophysiological methods cannot be applied here, and possible tools are rather limited.…”

Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors

“…In the adult peripheral nervous system, activation of ionotropic GABA A receptors (GABA A R) can cause neuron excitation because of the high concentration of intracellular chloride in these neurons (for review see [ 51 ]). Potassium-chloride cotransporters (KCCs) appear to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury [ 52 ].…”

Novel Analgesics with Peripheral Targets

“…Intraneuronal chloride homeostasis is maintained by multiple players, and the outline of a topical review [245] has been used here to focus on analgesic potential. Chloride channels are comprised of GABAA and glycine receptors, calciumactivated chloride channels (CaCC), ClC family of chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR), volume-regulated anion channels (VRAC), and maxi-anion channels.…”