Redox and nitric oxide-mediated regulation of sensory neuron ion channel function

Abstract

Significance: Reactive oxygen and nitrogen species (ROS and RNS, respectively) can intimately control neuronal excitability and synaptic strength by regulating the function of many ion channels. In peripheral sensory neurons, such regulation contributes towards the control of somatosensory processing; therefore, understanding the mechanisms of such regulation is necessary for the development of new therapeutic strategies and for the treatment of sensory dysfunctions, such as chronic pain.

Recent advances: Tremendous progress in deciphering nitric oxide (NO) and ROS signaling in the nervous system has been made in recent decades. This includes the recognition of these molecules as important second messengers and the elucidation of their metabolic pathways and cellular targets. Mounting evidence suggests that these targets include many ion channels which can be directly or indirectly modulated by ROS and NO. However, the mechanisms specific to sensory neurons are still poorly understood. This review will therefore summarize recent findings that highlight the complex nature of the signaling pathways involved in redox/NO regulation of sensory neuron ion channels and excitability; references to redox mechanisms described in other neuron types will be made where necessary.

Critical issues: The complexity and interplay within the redox, NO, and other gasotransmitter modulation of protein function are still largely unresolved. Issues of specificity and intracellular localization of these signaling cascades will also be addressed.

Future directions: Since our understanding of ROS and RNS signaling in sensory neurons is limited, there is a multitude of future directions; one of the most important issues for further study is the establishment of the exact roles that these signaling pathways play in pain processing and the translation of this understanding into new therapeutics.

FIG. 1.

Simplified anatomy of the peripheral somatosensory system. (A) Sensory fibers within the peripheral somatosensory system detect thermal, chemical, tactile, and damage-related (nociceptive) stimuli within skin, viscera, muscles, etc., and convey this information to the spinal cord. The fibers are composed of the axons of peripheral sensory neurons whose cell bodies reside within peripheral ganglia (such as DRG, TG, or nodose ganglia). The axons form nerve endings with peripheral organs and synapses in the spinal cord. (B) Peripheral sensory neurons represent some of the longest cells within our bodies. The relative size of a cell body compared with the axon of a DRG neuron innervating hindlimb skin in humans is illustrated; adapted from Devor (43) with permission. DRG, dorsal root ganglia; TG, trigeminal ganglia.

FIG. 2.

Schematic representation of ROS generation in mitochondria. The main sites of ROS generation within mitochondrial ETC are ETC complexes I and III (complexes I to V are represented by gray shapes and labeled accordingly). O₂^•− is formed by molecular oxygen reacting with the electrons from the ETC. In the mitochondrial matrix, O₂^•− is converted to H₂O₂ by MnSOD. H₂O₂ can then be reduced to H₂O and O₂ by catalase or through glutathione/thioredoxin reduction pathways. In the intermembrane space of mitochondria, O₂^•− can be generated at complex III, where it is reduced to H₂O₂ by CuSOD and ZnSOD. Based on the generalizations provided in Refs. (118, 196). IMM, inner mitochondrial membrane; GR, gluthathione reductase; GS, glutathione synthase; TR, thioredoxin; ETC, electron transport chain; MnSOD, manganese superoxide dismutase; CuSOD, copper superoxide dismutase; ZnSOD, zinc superoxide dismutase; ROS, reactive oxygen species; H₂O₂, hydrogen peroxide; O₂^•−, superoxide anion.

FIG. 3.

Catalytic action of cNOS. The binding of Ca²⁺ to calmodulin enables the flow of electrons through the reductase domain of cNOS. NADPH donates an electron (e⁻) to the reductase domain of cNOS, proceeding via FAD and FMN redox carriers to the oxgyenase domain. The e⁻ interacts with haem iron and BH4 at the active site to catalyze the reaction of O₂ with l-arginine, generating NO and l-citrulline as products. Low concentrations of the substrates or co-factors result in the uncoupling of cNOS with the e⁻ passed to O₂, resulting in cNOS generating O₂^•− in addition to NO. The O₂^•− and NO can readily react and produce ONOO⁻, a powerful oxidant. The uncoupled pathway leading to nitrosative stress is indicated by the gray arrows. cNOS, constitutive nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; O₂, oxygen; NO, nitric oxide; ONOO⁻, peroxynitrite anion; BH4, tetrahydrobiopterin.

FIG. 4.

Some isomerization and cleavage pathways of protonated ONOO⁻. Nitrosative stress-associated pathways are indicated by the bold gray arrows.

FIG. 5.

Modulation of M-type K⁺ channels by ROS and NO. (A) Schematic showing the domain structure and location of triplets of reactive cysteines within M channel subunits Kv7.2–7.5. Putative chemical modifications of the cysteines within the triplet are indicated with “SOH” denoting cysteine sulfenic acid formation and “SNO” denoting cysteine S-nitrosylaton. (B) Modification by ROS increases M-current, which leads to the inhibition of neuronal excitability (green); whereas NO-mediated modification suppresses M channel activity, leading to increased excitability (red).

FIG. 6.

Putative mechanisms of regulation of K_ATP channels by NO. NBD, nucleotide binding domain; NEM, N-ethylmaleimide; DTT, dithiothreitol; SNAP, S-nitroso-N-acetyl-DL-penicillamine; GC, guanylate cyclase; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G. Based on the data from Refs. (77, 122, 134).

FIG. 7.

Modulation of TRP channels by ROS and nitrosylation. (A) Model for TRP channel activation by NO and reactive disulfides (based on TRPC5 and proposed to be applicable to other NO-sensitive TRP channels, including TRPV1). Adapted from Yoshida et al. (222) with permission. (B) Reactive cysteine residues (black circles) of human TRPA1; adapted from Takahashi and Mori (188) with permission. TRP, transient receptor potential.

FIG. 8.

Cysteines involved in redox/NO modulation of NMDA receptors. Residues involved in redox and NO modulation are shown within the darker and lighter gray circles, respectively; residues that were implicated in both types of modulation are shown within the overlap of two circles. Based on data from Refs. (34, 35, 127, 184). NMDA, N-methyl-d-aspartate.