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Amitriptyline inhibits the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes

Title
Amitriptyline inhibits the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes
Authors
Baik H.-J.Lee S.-A.Washington J.M.Zuo Z.-Y.
Ewha Authors
백희정
SCOPUS Author ID
백희정scopus
Issue Date
2009
Journal Title
Journal of Pharmacy and Pharmacology
ISSN
0022-3573JCR Link
Citation
vol. 61, no. 5, pp. 577 - 581
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Objectives: Evidence suggests that glutamatergic systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. We have investigated the effects of amitriptyline, a tricyclic antidepressant, on the activity of the excitatory amino acid transporter type 3 (EAAT3), a protein that can regulate extracellular glutamate concentrations in the brain. Methods: EAAT3 was expressed in Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 μM L-glutamate in the presence or absence of various concentrations of amitriptyline or after application of various concentrations of L-glutamate in the presence or absence of 0.64 μM amitriptyline. Key findings: Amitriptyline concentration-dependently reduced EAAT3 activity. This inhibition reached statistical significance at 0.38-1.27 μM amitriptyline. Amitriptyline 0.64 μM reduced the pharmacokinetic parameter Vmax, but did not affect the pharmacokinetic parameter Km, of EAAT3 for L-glutamate. The amitriptyline inhibition disappeared after a 4-min washout. Phorbol-12-myristate-13-acetate, a protein kinase C activator, increased EAAT3 activity. However, 0.64 μM amitriptyline induced a similar degree of decrease in EAAT3 activity in the presence or absence of phorbol-12-myristate-13-acetate. Conclusions: Our results suggested that amitriptyline at clinically relevant concentrations reversibly reduced EAAT3 activity via decreasing its maximal velocity of glutamate transporting function. The effects of amitriptyline on EAAT3 activity may have represented a novel site of action for amitriptyline to increase glutamatergic neurotransmission. Protein kinase C may not have been involved in the effects of amitriptyline on EAAT3. © 2009 The Authors.
DOI
10.1211/jpp/61.05.0005
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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