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Titolo:
Pharmacological characterisation of the human small conductance calcium-activated potassium channel hSK3 reveals sensitivity to tricyclic antidepressants and antipsychotic phenothiazines
Autore:
Terstappen, GC; Pula, G; Carignani, C; Chen, MX; Roncarati, R;
Indirizzi:
GlaxoWellcome Med Res Ctr, Mol Biol & Biochem Unit, I-37135 Verona, Italy GlaxoWellcome Med Res Ctr Verona Italy I-37135 it, I-37135 Verona, Italy GlaxoWellcome Med Res Ctr, Dept Mol Pharmacol, Stevenage SG1 2NY, Herts, England GlaxoWellcome Med Res Ctr Stevenage Herts England SG1 2NY Herts, England Univ Verona, Dept Med & Publ Hlth, Pharmacol Sect, I-37134 Verona, Italy Univ Verona Verona Italy I-37134 , Pharmacol Sect, I-37134 Verona, Italy
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 6, volume: 40, anno: 2001,
pagine: 772 - 783
SICI:
0028-3908(200105)40:6<772:PCOTHS>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
CA2+-ACTIVATED K+ CHANNELS; MAMMALIAN-CELL LINES; HIPPOCAMPAL-NEURONS; SELECTIVE BLOCKER; PYRAMIDAL NEURONS; CA2+ CHANNELS; CAG REPEAT; HKCA3 GENE; APAMIN; BRAIN;
Keywords:
human small conductance calcium-activated potassium channel SK3 (hSK3); DiBAC(4)(3); [I-125]-apamin binding; tricyclic antidepressants; phenothiazines; protein phosphatase inhibitors;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Terstappen, GC GlaxoWellcome Med Res Ctr, Mol Biol & Biochem Unit, Via A Fleming 4, I-37135 Verona, Italy GlaxoWellcome Med Res Ctr Via A Fleming 4 Verona Italy I-37135
Citazione:
G.C. Terstappen et al., "Pharmacological characterisation of the human small conductance calcium-activated potassium channel hSK3 reveals sensitivity to tricyclic antidepressants and antipsychotic phenothiazines", NEUROPHARM, 40(6), 2001, pp. 772-783

Abstract

A stable CHO-K1 cell line was developed which expresses the human small conductance calcium-activated potassium channel hSK3. Immunofluorescence microscopy using an anti-SK3 antibody and radioligand binding using [I-125]-apamin demonstrated the presence of hSK3 channel in the recombinant cell line. This cell line was utilised in a fluorescence assay using the membrane potential-sensitive dye DiBAC(4)(3) to functionally analyse and pharmacologically characterise this potassium channel. The analysis of known blockers of calcium-activated potassium channels revealed the highest potency for apamin (IC50=13.2 nM). This result was confirmed by direct recordings of SK3 currents using the whole-cell patch-clamp technique. Tricyclic antidepressantssuch as desipramine. imipramine and nortriptyline as well as phenothiazines such as fluphenazine, promethazine, chlorpromazine and trifluoperazine blocked the hSK3 channel with micromolar potencies. These compounds also displaced [I-125]-apamin binding to the hSK3 channel thus suggesting direct andcompetitive channel blocking activity. Since these compounds: share a common three-ring molecular core structure, this feature seems to be important for channel blocking activity. The serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A were able to abolish channel activation with nanomolar potencies, but did not displace [I-125]-apamin binding. Thus, phosphorylation of hSK3 or an accessory channel subunit seems to be involved in its modulation. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 12:00:53