Inhibitory Actions of Synthesised Polyamine Spider Toxins and Their Analogues on Neuronal Voltage-Activated Calcium Currents
The whole cell variant of the patch-clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca 2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-...
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| Veröffentlicht in: | Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology Comparative pharmacology and toxicology, 1997, Vol.116 (1), p.23-32 |
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| container_title | Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology |
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| creator | Sutton, Kathy G Stapleton, Simon R Timms, Graham Gilmore, Jeremy Brust, Paul F Bleakman, David Scott, Roderick H |
| description | The whole cell variant of the patch-clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca
2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-FTX-3.3 (synthetic analogues of FTX) were studied using cultured dorsal root ganglion neurones from neonatal rats, C2D7 cells (HEK293 cells stably coexpressing recombinant human N-type voltage-activated Ca
2+ channel,
α
1B-1-
α
2b
δβ
1b subunits) and freshly isolated cerebellar Purkinje neurones. In dorsal root ganglion neurones, sFTX-3.3 (10
μM) inhibited high voltage-activated Ca
2+ currents evoked by depolarisations to 0 mV from a holding potential of −90 mV. Partial overlap in Ca
2+ current sensitivity to the polyamine sFTX-3.3 and the peptide spider toxin
ω-Aga IVA was observed. However, evidence also suggests sFTX-3.3 and
ω-Aga IVA do not show complete pharmacological overlap and that distinct parts of the Ca
2+ current are sensitive to one of two inhibitors. The arginine group on sFTX-3.3 appears to be important for its inhibitory action on Ca
2+ currents, because analogues where this amino acid was replaced with either ornithine (Orn-FTX-3.3) or lysine (Lys-FTX-3.3) were relatively inactive at concentrations below 1 mM. Synthesised FTX (100
μM) was inactive as an inhibitor of Ca
2+ currents recorded from dorsal root ganglion and only produced modest effects in Purkinje neurones and C2D7 cells. At a concentration of 1 mM, nonselective actions were observed that indicated that synthesised FTX and sFTX-3.3 could reversibly inhibit both N- and P-type Ca
2+ channels equally well. In conclusion, the potency of polyamines as nonselective inhibitors of Ca
2+ channels is in part determined by the presence of a terminal arginine, and this may involve an interaction between terminal guanidino groups with Ca
2+ binding sites. |
| doi_str_mv | 10.1016/S0742-8413(96)00141-7 |
| format | Article |
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2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-FTX-3.3 (synthetic analogues of FTX) were studied using cultured dorsal root ganglion neurones from neonatal rats, C2D7 cells (HEK293 cells stably coexpressing recombinant human N-type voltage-activated Ca
2+ channel,
α
1B-1-
α
2b
δβ
1b subunits) and freshly isolated cerebellar Purkinje neurones. In dorsal root ganglion neurones, sFTX-3.3 (10
μM) inhibited high voltage-activated Ca
2+ currents evoked by depolarisations to 0 mV from a holding potential of −90 mV. Partial overlap in Ca
2+ current sensitivity to the polyamine sFTX-3.3 and the peptide spider toxin
ω-Aga IVA was observed. However, evidence also suggests sFTX-3.3 and
ω-Aga IVA do not show complete pharmacological overlap and that distinct parts of the Ca
2+ current are sensitive to one of two inhibitors. The arginine group on sFTX-3.3 appears to be important for its inhibitory action on Ca
2+ currents, because analogues where this amino acid was replaced with either ornithine (Orn-FTX-3.3) or lysine (Lys-FTX-3.3) were relatively inactive at concentrations below 1 mM. Synthesised FTX (100
μM) was inactive as an inhibitor of Ca
2+ currents recorded from dorsal root ganglion and only produced modest effects in Purkinje neurones and C2D7 cells. At a concentration of 1 mM, nonselective actions were observed that indicated that synthesised FTX and sFTX-3.3 could reversibly inhibit both N- and P-type Ca
2+ channels equally well. In conclusion, the potency of polyamines as nonselective inhibitors of Ca
2+ channels is in part determined by the presence of a terminal arginine, and this may involve an interaction between terminal guanidino groups with Ca
2+ binding sites.</description><identifier>ISSN: 0742-8413</identifier><identifier>DOI: 10.1016/S0742-8413(96)00141-7</identifier><language>eng</language><publisher>Elsevier Inc</publisher><subject>Cultured neurones ; high voltage-activated calcium channels ; polyamines ; spider toxins ; synthesised FTX ; ω-Agatoxin IVA</subject><ispartof>Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology, 1997, Vol.116 (1), p.23-32</ispartof><rights>1997 Elsevier Science Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c286t-dcde82e8ee61c3d3370102ea41812bb04a040e62ac7e60f2579f632829a2cfce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4009,27902,27903,27904</link.rule.ids></links><search><creatorcontrib>Sutton, Kathy G</creatorcontrib><creatorcontrib>Stapleton, Simon R</creatorcontrib><creatorcontrib>Timms, Graham</creatorcontrib><creatorcontrib>Gilmore, Jeremy</creatorcontrib><creatorcontrib>Brust, Paul F</creatorcontrib><creatorcontrib>Bleakman, David</creatorcontrib><creatorcontrib>Scott, Roderick H</creatorcontrib><title>Inhibitory Actions of Synthesised Polyamine Spider Toxins and Their Analogues on Neuronal Voltage-Activated Calcium Currents</title><title>Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology</title><description>The whole cell variant of the patch-clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca
2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-FTX-3.3 (synthetic analogues of FTX) were studied using cultured dorsal root ganglion neurones from neonatal rats, C2D7 cells (HEK293 cells stably coexpressing recombinant human N-type voltage-activated Ca
2+ channel,
α
1B-1-
α
2b
δβ
1b subunits) and freshly isolated cerebellar Purkinje neurones. In dorsal root ganglion neurones, sFTX-3.3 (10
μM) inhibited high voltage-activated Ca
2+ currents evoked by depolarisations to 0 mV from a holding potential of −90 mV. Partial overlap in Ca
2+ current sensitivity to the polyamine sFTX-3.3 and the peptide spider toxin
ω-Aga IVA was observed. However, evidence also suggests sFTX-3.3 and
ω-Aga IVA do not show complete pharmacological overlap and that distinct parts of the Ca
2+ current are sensitive to one of two inhibitors. The arginine group on sFTX-3.3 appears to be important for its inhibitory action on Ca
2+ currents, because analogues where this amino acid was replaced with either ornithine (Orn-FTX-3.3) or lysine (Lys-FTX-3.3) were relatively inactive at concentrations below 1 mM. Synthesised FTX (100
μM) was inactive as an inhibitor of Ca
2+ currents recorded from dorsal root ganglion and only produced modest effects in Purkinje neurones and C2D7 cells. At a concentration of 1 mM, nonselective actions were observed that indicated that synthesised FTX and sFTX-3.3 could reversibly inhibit both N- and P-type Ca
2+ channels equally well. In conclusion, the potency of polyamines as nonselective inhibitors of Ca
2+ channels is in part determined by the presence of a terminal arginine, and this may involve an interaction between terminal guanidino groups with Ca
2+ binding sites.</description><subject>Cultured neurones</subject><subject>high voltage-activated calcium channels</subject><subject>polyamines</subject><subject>spider toxins</subject><subject>synthesised FTX</subject><subject>ω-Agatoxin IVA</subject><issn>0742-8413</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNqFkE9LAzEQxXNQsFY_gpCT6GE1yW6zuycpxT-FokKr15BmZ9vIblKTbHHBD2_aildPA2_e-zHzELqg5IYSym_nJM9YUmQ0vSr5NSE0o0l-hAZ_8gk69f6DxA2jfIC-p2atlzpY1-OxCtoaj22N570Ja_DaQ4VfbdPLVhvA842uwOGF_dLRJk2FF2vQDo-NbOyqgxg1-Bk6Z6OA320T5AqSHXYrQyRNZKN01-JJ5xyY4M_QcS0bD-e_c4jeHu4Xk6dk9vI4nYxniWIFD0mlKigYFACcqrRK05xQwkBmtKBsuSSZJBkBzqTKgZOajfKy5ikrWCmZqhWkQ3R54G6c_YxnBtFqr6BppAHbeUE5pZFFonF0MCpnvXdQi43TrXS9oETs-hX7fsWuSFFyse9X5DF3d8hB_GKrwQmvNBgFlXaggqis_ofwAyeDhn8</recordid><startdate>1997</startdate><enddate>1997</enddate><creator>Sutton, Kathy G</creator><creator>Stapleton, Simon R</creator><creator>Timms, Graham</creator><creator>Gilmore, Jeremy</creator><creator>Brust, Paul F</creator><creator>Bleakman, David</creator><creator>Scott, Roderick H</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>1997</creationdate><title>Inhibitory Actions of Synthesised Polyamine Spider Toxins and Their Analogues on Neuronal Voltage-Activated Calcium Currents</title><author>Sutton, Kathy G ; Stapleton, Simon R ; Timms, Graham ; Gilmore, Jeremy ; Brust, Paul F ; Bleakman, David ; Scott, Roderick H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c286t-dcde82e8ee61c3d3370102ea41812bb04a040e62ac7e60f2579f632829a2cfce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Cultured neurones</topic><topic>high voltage-activated calcium channels</topic><topic>polyamines</topic><topic>spider toxins</topic><topic>synthesised FTX</topic><topic>ω-Agatoxin IVA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sutton, Kathy G</creatorcontrib><creatorcontrib>Stapleton, Simon R</creatorcontrib><creatorcontrib>Timms, Graham</creatorcontrib><creatorcontrib>Gilmore, Jeremy</creatorcontrib><creatorcontrib>Brust, Paul F</creatorcontrib><creatorcontrib>Bleakman, David</creatorcontrib><creatorcontrib>Scott, Roderick H</creatorcontrib><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sutton, Kathy G</au><au>Stapleton, Simon R</au><au>Timms, Graham</au><au>Gilmore, Jeremy</au><au>Brust, Paul F</au><au>Bleakman, David</au><au>Scott, Roderick H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitory Actions of Synthesised Polyamine Spider Toxins and Their Analogues on Neuronal Voltage-Activated Calcium Currents</atitle><jtitle>Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology</jtitle><date>1997</date><risdate>1997</risdate><volume>116</volume><issue>1</issue><spage>23</spage><epage>32</epage><pages>23-32</pages><issn>0742-8413</issn><abstract>The whole cell variant of the patch-clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca
2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-FTX-3.3 (synthetic analogues of FTX) were studied using cultured dorsal root ganglion neurones from neonatal rats, C2D7 cells (HEK293 cells stably coexpressing recombinant human N-type voltage-activated Ca
2+ channel,
α
1B-1-
α
2b
δβ
1b subunits) and freshly isolated cerebellar Purkinje neurones. In dorsal root ganglion neurones, sFTX-3.3 (10
μM) inhibited high voltage-activated Ca
2+ currents evoked by depolarisations to 0 mV from a holding potential of −90 mV. Partial overlap in Ca
2+ current sensitivity to the polyamine sFTX-3.3 and the peptide spider toxin
ω-Aga IVA was observed. However, evidence also suggests sFTX-3.3 and
ω-Aga IVA do not show complete pharmacological overlap and that distinct parts of the Ca
2+ current are sensitive to one of two inhibitors. The arginine group on sFTX-3.3 appears to be important for its inhibitory action on Ca
2+ currents, because analogues where this amino acid was replaced with either ornithine (Orn-FTX-3.3) or lysine (Lys-FTX-3.3) were relatively inactive at concentrations below 1 mM. Synthesised FTX (100
μM) was inactive as an inhibitor of Ca
2+ currents recorded from dorsal root ganglion and only produced modest effects in Purkinje neurones and C2D7 cells. At a concentration of 1 mM, nonselective actions were observed that indicated that synthesised FTX and sFTX-3.3 could reversibly inhibit both N- and P-type Ca
2+ channels equally well. In conclusion, the potency of polyamines as nonselective inhibitors of Ca
2+ channels is in part determined by the presence of a terminal arginine, and this may involve an interaction between terminal guanidino groups with Ca
2+ binding sites.</abstract><pub>Elsevier Inc</pub><doi>10.1016/S0742-8413(96)00141-7</doi><tpages>10</tpages></addata></record> |
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| identifier | ISSN: 0742-8413 |
| ispartof | Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology, 1997, Vol.116 (1), p.23-32 |
| issn | 0742-8413 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_16111810 |
| source | Alma/SFX Local Collection |
| subjects | Cultured neurones high voltage-activated calcium channels polyamines spider toxins synthesised FTX ω-Agatoxin IVA |
| title | Inhibitory Actions of Synthesised Polyamine Spider Toxins and Their Analogues on Neuronal Voltage-Activated Calcium Currents |
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