The Effect of Structural Analogues of Etimizole on Protein Kinase CK2, Protein Phosphorylation, and Transcription of Chr
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e Effect of Structural Analogues of Etimizole on Protein Kinase CK2, Protein Phosphorylation, and Transcription of Chromatin in Rat Cortical and Hippocampal Neurons B. A. Reikhardta, * and P. D. Shabanova a
Institute of Experimental Medicine, ul. Akad. Pavlova 12, St. Petersburg, 197376 Russia *e-mail: [email protected] Received October 24, 2019; revised April 21, 2020; accepted April 21, 2020
Abstract—The multifunctional protein kinase CK2 is an important enzyme in the nervous system. The nuclear forms of CK2 regulate chromatin structure and gene expression, the key processes for long-term memory formation. In vitro memory modulators, Structural Analogues of Etimizole (SAE), were able to increase or decrease the chromatin-associated CK2 activity in the rat brain cortex and hippocampus. In vivo administration of memory enhancers from SAE-group (3 mg/kg) stimulated CK2 activity and the transcriptional ability of chromatin in the cortex and hippocampus; the effect was observed 30 min after administration, reached a peak at 60 min and lasted for 180 min. At these periods the memory inhibitor from the SAEgroup reduced CK2 activity and chromatin transcription. It is assumed that the modulating effect of SAEs on CK2 activity and transcription underlies the effects of these compounds on long-term memory. Keywords: brain, long-term memory, chromatin, transcription, protein phosphorylation, protein kinase CK2 DOI: 10.1134/S1990750820040101
INTRODUCTION The protein kinase CK2 (casein kinase 2, EC 2.7.11.1) is ubiquitously expressed in mammalian tissues, especially in the hippocampus, where its activity is 3−4 times higher than in other tissues [1–3]. The holoenzyme CK2 (α2β2) is composed of two catalytic (α) and two regulatory subunits (β) and is localized mainly in the nucleus. Besides α2β2, free CK2αmonomers have been found in the cytosol [4, 5]. CK2α is synthesized de novo in a catalytically active form and does not require phosphorylation or second Abbreviations used: AC—adenylate cyclase; AR—androgen receptor; Akt/PKB—serine/threonine protein kinase B; BSA— bovine serum albumin; CaMK—Ca/Calmodulin-dependent protein kinase; CDKs—cyclin-dependent protein kinases; CK1—casein kinase 1; DARPP32—dopamine and cAMP regulated phosphoprotein 32-kDa; ER—estrogen receptor; Erk1/2— extracellular signal-regulated kinase; HDAC1—histone deacetylase 1; HP1—heterochromatin protein 1, HMG14/HMGN1— non-histone chromosomal protein of High Mobility Group 14family or High Mobility Group-family Nucleosome Binding Domain 1 containing protein; IR—insulin receptor; Jnk—c-Jun N-terminal kinase; LTM—long-term memory; PKA—protein kinase A; PKC—protein kinase C; PMSF—phenylmethylsulfonyl fluoride; PP2B—protein phosphatase 2B; PP2C—protein phosphatase 2C; RAF-ERK—the signaling pathway of stress and mitogen-activated protein kinases, transducing the signal from Raf1/A/B protein kinases to effector kinases; PR—progesterone receptor; SAE—structural analogues of etimizole; TAC— transcriptional activity of chromatin; TCA—trichloroacetic acid; TR—thyroid h
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