30
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Allosteric interactions between receptor site 3 and 4 of voltage-gated sodium channels: a novel perspective for the underlying mechanism of scorpion sting-induced pain

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          AbstractBackground BmK I, a site-3-specific modulator of voltage-gated sodium channels (VGSCs), causes pain and hyperalgesia in rats, while BmK IT2, a site-4-specific modulator of VGSCs, suppresses pain-related responses. A stronger pain-related effect has been previously attributed to Buthus martensi Karsch (BmK) venom, which points out the joint pharmacological effect in the crude venom.Methods In order to detect the joint effect of BmK I and BmK IT2 on ND7-23 cells, the membrane current was measured by whole cell recording. BmK I and BmK IT2 were applied successively and jointly, and the synergistic modulations of VGSCs on ND7-23 cells were detected.Results Larger peak I Na and more negative half-activation voltage were elicited by joint application of BmK I and BmK IT2 than by application of BmK I or BmK IT2 alone. Compared to the control, co-applied BmK I and BmK IT2 also significantly prolonged the time constant of inactivation.Conclusions Our results indicated that site-4 toxin (BmK IT2) could enhance the pharmacological effect induced by site-3 toxin (BmK I), suggesting a stronger effect elicited by both toxins that alone usually exhibit opposite pharmacological effects, which is related to the allosteric interaction between receptor site 3 and site 4. Meanwhile, these results may bring a novel perspective for exploring the underlying mechanisms of scorpion sting-induced pain.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          Deconstructing voltage sensor function and pharmacology in sodium channels

          Voltage-activated sodium (Nav) channels are crucial for the generation and propagation of nerve impulses, and as such are amongst the most widely targeted ion channels by toxins and drugs. The four voltage sensors in Nav channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (Kv) channels as reporters to examine the contributions of individual Nav channel S3b-S4 paddle motifs to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Nav channels and reveal how paddle-specific interactions can be used to reshape Nav channel activity. One paddle motif is unique in that it slows voltage sensor activation and toxins selectively targeting this motif impede Nav channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Nav channelopathies.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Inherited disorders of voltage-gated sodium channels.

            A variety of inherited human disorders affecting skeletal muscle contraction, heart rhythm, and nervous system function have been traced to mutations in genes encoding voltage-gated sodium channels. Clinical severity among these conditions ranges from mild or even latent disease to life-threatening or incapacitating conditions. The sodium channelopathies were among the first recognized ion channel diseases and continue to attract widespread clinical and scientific interest. An expanding knowledge base has substantially advanced our understanding of structure-function and genotype-phenotype relationships for voltage-gated sodium channels and provided new insights into the pathophysiological basis for common diseases such as cardiac arrhythmias and epilepsy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.

              Voltage-gated sodium channels are the molecular targets for a broad range of neurotoxins that act at six or more distinct receptor sites on the channel protein. These toxins fall into three groups. Both hydrophilic low molecular mass toxins and larger polypeptide toxins physically block the pore and prevent sodium conductance. Alkaloid toxins and related lipid-soluble toxins alter voltage-dependent gating of sodium channels via an allosteric mechanism through binding to intramembranous receptor sites. In contrast, polypeptide toxins alter channel gating by voltage sensor trapping through binding to extracellular receptor sites. The results of recent studies that define the receptor sites and mechanisms of action of these diverse toxins are reviewed here.
                Bookmark

                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                jvatitd
                Journal of Venomous Animals and Toxins including Tropical Diseases
                J. Venom. Anim. Toxins incl. Trop. Dis
                Centro de Estudos de Venenos e Animais Peçonhentos - CEVAP, Universidade Estadual Paulista - UNESP (Botucatu )
                1678-9199
                2015
                : 21
                : 0
                : 5
                Affiliations
                [1 ] Shanghai University China
                [2 ] Shanghai University China
                [3 ] Fudan University China
                [4 ] Baylor College of Medicine United States
                Article
                S1678-91992015000100347
                10.1186/s40409-015-0043
                f93f44c0-e27c-4e22-aefa-ee2ab0d5ad5f

                http://creativecommons.org/licenses/by/4.0/

                History
                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=1678-9199&lng=en
                Categories
                TOXICOLOGY
                TROPICAL MEDICINE

                Toxicology,Infectious disease & Microbiology
                BmK I,BmK IT2,Synergistic effect,Allosteric interactions

                Comments

                Comment on this article