Biology subjects

Comes, N.

Publications and source records attributed to Comes, N..

3 recordsLinked to original sources

bioRxiv2025

KCNK18 c.1107del frameshift in peripheral neuropathy links TRESK dysfunction to neuropathic pain

Neuropathic pain is commonly accompanied by hyperexcitability of nociceptive neurons, which is driven by regulation of several ion channels, including two-pore domain potassium channels (K2P) that stabilize the resting membrane potential. The TWIK-Related Spinal cord potassium channel (TRESK, K2p18.1) is predominantly expressed in sensory ganglia, where it provides major background K conductance. We describe a heterozygous c.1107del frameshift mutation in KCNK18, encoding TRESK, found in a patient with painful small fiber neuropathy and dysautonomia. This C-terminal c.1107del mutant is predicted to generate an elongated C-terminal domain, with an altered protein sequence. Whole-cell patch calmp recordings showed that the c.1107del variant reduced K current density, while heterozygous-like expression resulted in intermediate currents, consistent with a haploinsufficiency mechanism. Confocal imaging revealed decreased plasma membrane expression, indicating a trafficking-dependent loss of function while oligomerization with TRESK (homomeric channels) or TREK1 remained intact. In silico analysis revealed an altered phosphorylation pattern and reduced C-terminal hydrophobicity in the mutant TRESK. Overall, these findings support c.1107del as a pathogenic KCNK18 variant causing TRESK haploinsufficiency, offering mechanistic insight into the pathophysiology of neuropathic pain.

neuroscience↗

bioRxiv2024

TRESK background potassium channel in MrgprA3+ pruriceptors regulates acute and chronic itch.

TRESK (K2P18.1) is a background K+ channel expressed in sensory neurons, where it modulates the resting membrane potential, action potential firing and neuronal excitability. A subset of these sensory neurons, which express specific TRPs and Mas-related G protein-coupled receptors (Mrgprs), are activated by pruritogens and mediate itch sensations. Because TRESK is involved in somatosensation and pain transduction, we evaluated the contribution of this channel to pruritic sensitivity and its potential as a target for the treatment of chronic itch pathologies. By combining RNA in situ hybridization, calcium imaging, electrophysiological and behavioral approaches, we found that TRESK is involved in the modulation of non-histaminergic itch. TRESK is coexpressed with MrgprD+ and MrgprA3+ in sensory neurons and MrgprA3+ neurons from TRESK-/- animals display an enhanced firing compared to WT counterparts. Interestingly, acute itch to intradermal injection of chloroquine is significantly enhanced in the absence of TRESK but not the response to histamine, BAM8-22 or LTC4. TRESK deletion also enhanced chronic itch in mice models of Allergic Contact Dermatitis and Dry Skin. In the mouse model imiquimod-induced psoriasiform dermatitis, the absence of TRESK produced a significantly enhanced scratching behavior, which developed earlier and was more robust. Finally, enhancing TRESK function with the channel activator cloxyquin diminished both acute and chronic itch in WT mice but not in KO animals. In summary, our data indicates that TRESK is involved in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitutes a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic itch, for which appropriate treatments are lacking.

neuroscience↗

bioRxiv2019

TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Changes in TRESK K+ channel expression/function enhance sensory neurons excitability, but its role in somatosensory perception and nociception is poorly understood. We show that TRESK regulates the sensitivity to mechanical and cold stimuli but not the perception of heat. TRESK knockout mice nociceptive neurons present an enhanced excitability; skin nociceptive C-fibers show an increased activation by lower intensity cold or mechanical stimulation and mice lacking TRESK present mechanical and cold hypersensitivity. TRESK is also involved in osmotic pain and in early phases of formalin-induced inflammatory pain, but not in the development of mechanical and heat hyperalgesia during chronic pain. In contrast, mice lacking TRESK present cold allodynia that is not further enhanced by oxaliplatin. In summary, genetic removal of TRESK uncovers enhanced mechanical and cold sensitivity, indicating that it regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold-sensing, acting as a brake to prevent activation by low-intensity stimuli.

neuroscience↗