{"id":17700,"date":"2025-07-08T12:58:28","date_gmt":"2025-07-08T12:58:28","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=17700"},"modified":"2025-07-08T13:00:30","modified_gmt":"2025-07-08T13:00:30","slug":"2025-a-hydrophobic-loop-of-the-spider-venom-peptide-tl1a-drives-activity-at-nav1-8","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2025-a-hydrophobic-loop-of-the-spider-venom-peptide-tl1a-drives-activity-at-nav1-8\/","title":{"rendered":"2025 &#8211; A hydrophobic loop of the spider-venom peptide Tl1a drives activity at NaV1.8"},"content":{"rendered":"<p>Voltage-gated sodium (Na<sub>V<\/sub>s) channels are pore-forming transmembrane proteins that regulate the influx of sodium ions across cell membranes. Spider venoms are a rich source of Na<sub>V<\/sub>-modulating peptides with high selectivity and potency, making them important tools for understanding Na<sub>V<\/sub>\u00a0structure and function. Na<sub>V<\/sub>1.8 is tetrodotoxin-resistant, expressed in the peripheral nervous system and contributes to the propagation of action potentials in nociceptive neurons, making it a potential therapeutic target for pain. We identified Tl1a, a 36 amino acid residue peptide isolated from the crude venom of the Peruvian tarantula species\u00a0<em>Thrixopelma longicolli<\/em>\u00a0as a modulator of Na<sub>V<\/sub>1.8. Tl1a was synthesized using solid-phase peptide synthesis, and activity was assessed using automated whole-cell patch-clamp recordings. Tl1a inhibited Na<sub>V<\/sub>1.8 peak current (IC<sub>50<\/sub>\u00a0210\u00a0nM), delayed the kinetics of activation, inhibited fast inactivation, and caused a persistent current as well as a depolarising shift in the voltage dependence of activation (\u0394V<sub>1\/2<\/sub>\u00a0+11\u00a0mV). Tl1a inhibited peak current with similar potency at Na<sub>V<\/sub>1.5 (IC<sub>50<\/sub>\u00a0282\u00a0nM) and K<sub>V<\/sub>2.1 (IC<sub>50<\/sub>\u00a0156\u00a0nM) and was 8-fold selective over the tetrodotoxin-sensitive Na<sub>V<\/sub>1.4 (IC<sub>50<\/sub>\u00a01769\u00a0nM), Na<sub>V<\/sub>1.1 (2201\u00a0nM) and 6-fold selective over Na<sub>V<\/sub>1.7 (IC<sub>50<\/sub>\u00a01278\u00a0nM) channels. Tl1a analogues with an increased number of charged amino acids in loop 4 of the peptide lost activity at Na<sub>V<\/sub>1.8 due to altered interactions with the domain IV S3-S4 extracellular loop. The results of this work contribute to a better understanding of the structure-activity relationships at tetrodotoxin-resistant Na<sub>V<\/sub>\u00a0channels and may be useful for the future rational design of selective Na<sub>V<\/sub>1.8 peptide modulators.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[56,143],"target_categories":[61],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-17700","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-pain","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/17700","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=17700"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=17700"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=17700"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=17700"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=17700"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=17700"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=17700"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=17700"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=17700"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}