Title:Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders
Volume: 18
Issue: 11
Author(s): Elizabeth Kulikova and Alexander Kulikov*
Affiliation:
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 avenue Lavrentyev, 630090, Novosibirsk,Russian Federation
Keywords:
STEP, TC-2153, depression, antidepressant, serotonin, BDNF, NMDA receptors.
Abstract: Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its
dysregulation is associated with Alzheimer’s and Huntington’s diseases, schizophrenia, fragile X syndrome,
drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders
is still obscure. The review discusses the theoretical foundations and experimental facts concerning
possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates
several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2
(ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and
AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived
neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results
in progressive degeneration of neurons in the hippocampus and cortex and increases depression
risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride
(TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike
behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a
promising molecular target for atypical antidepressant drugs of new generation.
