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Advances in the Study of NALCN Involvement in Neuropathic Pain Mechanisms

Neuropathic pain (NP) is pain resulting from trauma or disease of the somatosensory system. This particular type of chronic pain affects 7-10% of the global population. However, due to the diverse etiology and complex pathogenesis of NP, there is no specific therapeutic target, and drug therapy is unsatisfactory. Therefore, it is important to reveal the pathogenesis of NP and explore the targets for NP treatment.

Sodium leak channel non-selective protein (NALCN) is a non-selective cation channel against river herring toxin, which generates a "leaky" Na+ inward current under physiological conditions. NALCN is widely expressed in the central nervous system and is involved in the regulation of neuronal excitation. NALCN is widely expressed in the central nervous system and is involved in the regulation of neuronal excitability. A recent study suggests that NALCN may be involved in nociceptive processing by enhancing the intrinsic excitability of spinal projection neurons. It is evident that NALCN plays an important role in pain generation and transmission and is expected to be a new target for the treatment of NP.

Creative Biolabs describes the structure and function of NALCN and its involvement in NP through various signaling pathways. For scientists in neuropathic pain research, we also provide the following related services.

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Structure of NALCN

NALCN is a human orphan channel, a unique branch of the four-structural-domain ion channel superfamily, which includes the widely studied voltage-gated sodium and voltage-gated calcium channels. These channels consist of four homologous structural domains, each with six transmembrane segments (S1~S6). NALCN, together with FAM155, UNC79, UNC80, and other proteins, forms the NALCN complex.

  • NALCN is the voltage-sensitive, pore-forming subunit of the complex.
  • FAM155A can act as a chaperone to promote NALCN folding and transmembrane.
  • UNC79 and UNC80 belong to the regulatory subunits and regulate the localization and function of the NALCN channel complex.

Structure of NALCN. (Monteil, Arnaud, et al., 2024)Fig. 1 Structure of NALCN.1

NALCN has several unique biophysical properties.

  • Non-inactivating - NALCN is a non-inactivating cation channel that mediates neuronal background Na+ "leak" currents.
  • Non-voltage dependence - NALCN has a linear current-voltage relationship over a test range of -100 mV to +100 mV. The reason for the non-voltage dependence of NALCN may be due to the absence of some charged residues in the S4 fragment of NALCN.
  • Non-selectivity - NALCN was permeable to Na+, K+, and Ca2+, but was mainly permeable to Na+.

Function of NALCN

  • Regulation of neuronal excitability: NALCN mediates the Na+ inward current, positively regulates the neuronal resting membrane potential depolarization, and determines the basal excitability of the neuron.
    Most mammalian neurons have a resting membrane potential of -50 to 80 mV, with a maximum depolarization close to the K+ equilibrium potential (-92 mV). This suggests the presence of resting conductances other than the resting potassium conductance. It was found that
    • NALCN was found to be a Na+ "leakage" current channel for river herring toxin resistance in mouse hippocampal neurons.
    • In hydrostatic snails, knockdown of NALCN in pacing neurons hyperpolarized the resting membrane potential by about 15 mV.
    • NALCN also has an important role in the maintenance of resting membrane potential in snail and nematode pacemaker neurons.
  • Involvement in neuronal spontaneous firing: Many neurons exhibit basal Na+ conductance at rest and are involved in the regulation of spontaneous firing and pacemaker activity. NALCN is involved in such tonic currents in some types of neurons and plays a key role in their excitability.
    • Spontaneous activity of dopaminergic neurons is almost always observed in wild-type mice, but spontaneous activity of dopaminergic neurons is almost silent in NALCN knockout mice.
    • NALCN provides a timed depolarization drive for circadian pacemaker neurons involved in regulating the daily rhythms of sleep and wakefulness. Neurons in the substantia nigra pars reticulata were found to express NALCN by single-cell RNA sequencing, and spontaneous firing was impaired in neurons in the substantia nigra pars reticulata lacking NALCN.
Mechanisms Descriptions Performances
Mechanism of Peripheral Sensitization Peripheral sensitization refers to the increased sensitivity of injury receptor neurons to afferent signals, manifested by overexcitation of primary afferent neurons and their decreased activation thresholds, and is an important mechanism of peripheral nerve-mediated nociceptive hypersensitivity.
  • NALCN channel expression was up-regulated on DRG neurons in rats with NP, and with the increase of NALCN expression and current function, DRG neurons were overexcited, and the mechanical pain threshold and thermal pain threshold of rats were decreased.
  • Inhibition of NALCN expression in the DRG significantly attenuated mechanical nociceptive hypersensitivity and thermal nociceptive hypersensitivity in NP rats.
Central Sensitization Mechanism Central sensitization refers to the enhanced response of injury-sensing neurons in the central nervous system to normal or subthreshold stimuli, which is mainly manifested as hyperexcitability of neurons in the dorsal horn of the spinal cord, and has been proven to be an important mechanism for the occurrence and development of NP.
  • NP development is associated with increased NALCN expression and function in the dorsal horn of the spinal cord.
  • NALCN can be involved in the onset and development of NP by mediating changes in Ca2+ concentration to cause the release of the excitatory neurotransmitter glutamate at the synapse.
Modulation of the Analgesic Effects of SP SP is a neuropeptide recognized to mediate pain. Studies have shown that SP secretion increases in various pain states, including NP.
  • NALCN can be activated by SP.
  • SP releases injurious signals to the spinal cord partly mediated through NALCN expressed within spinal cord dorsal horn neurons.
cAMP/PKA Signaling Pathway The cAMP/PKA signaling pathway regulates many cellular physiological processes, such as metabolism, cell growth and cell differentiation, as well as the expression of ion channels.
  • The cAMP/PKA signaling pathway is associated with NP.

NALCN may be a potential molecular target for the treatment of NP. In view of the important role of NALCN in the process of NP occurrence and development, using NALCN as a potential target for research and exploring in depth the possible mechanisms of NALCN involved in the occurrence and development of NP may provide a valuable theoretical basis for further revealing the mechanism of NP occurrence and development, as well as for the development of drugs for the treatment of NP.

Reference

  1. Monteil, Arnaud, et al. "New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN." Physiological Reviews 104.1 (2024): 399-472.

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