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Cross-Talk of the Glutamate and Leptin Receptor Pathways

  • STRUCTURAL–FUNCTIONAL ANALYSIS OF BIOPOLYMERS AND THEIR COMPLEXES
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Abstract

The hormone leptin is produced in adipocytes of white adipose tissue and crosses the blood–brain barrier. Leptin receptors are present in the brain regions that are involved in higher cognitive functions. In particular, leptin directly influences the glutamate receptor trafficking in CA3 → CA1 synapses to increase the phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) level, which is controlled by phosphoinositide 3-kinase (PI3K). It is well recognized that glutamate receptor trafficking involves at least some components of the insulin signaling cascade. However, the effects of leptin and insulin hormones differ at the cell and behavioral levels and often oppose each other. The domain organization of synaptic proteins was analyzed for CA1 field neurons. A molecular mechanism of leptin effects in the hippocampus was assumed to involve a cross-talk of the molecular pathways of the leptin receptors and NMDA-type glutamate receptors. Non-receptor protein kinases of the Src subfamily and, in particular, kinase Fyn are part of glutamate receptor macrocomplexes and are involved in regulating the efficiency of synaptic transmission. Fyn was assumed to utilize its SH2 domain to interact with leptin receptors directly or through other proteins and contribute to leptin signaling through the PI3K signaling pathway. The hypothesis explains experimental findings and sheds further light on the fine tuning of hormone-dependent modulation of hippocampal synaptic processes.

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Funding

The work utilized the materials obtained in a basic research project of the Russian Academy of Sciences (project no. VI.35.2.6).

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Authors and Affiliations

  1. Federal Research Center of Information and Computational Technologies, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    A. L. Proskura, M. Yu. Islamova & S. O. Vechkapova

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  1. A. L. Proskura
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  2. M. Yu. Islamova
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  3. S. O. Vechkapova
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Correspondence to A. L. Proskura.

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The authors declare that they have no conflict of interest. This work does not contain any studies involving animals or human subjects performed by any of the authors.

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Translated by T. Tkacheva

Abbreviations: NMDA, N-methyl D-aspartate; AMPA, α‑amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDAR, NMDA receptor; AMPAR, AMPA receptor; LTP, long-term potentiation; GluR1 and GluR2/3, AMPAR subunits; IRS, insulin receptor substrate; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PKC, protein kinase C; PI5K, phosphoinositide 5-kinase; p85 and p110, regulatory and catalytic subunits of PI3K, respectively; Fyn, non-receptor tyrosine protein kinase of the Src subfamily; SH3 and SH2, Src-like homology domains 3 and 2, respectively; PI4P, phosphatidylinositol 4-phosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; PI(4,5)P2, phosphatidylinositol 4,5-diphosphate; Jak2, Janus kinase 2; CK2, casein kinase 2; SHP2, tyrosine phosphatase 2; STAT3 and STAT5, signal transducers and activators of transcription 3 and 5, respectively.

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Proskura, A.L., Islamova, M.Y. & Vechkapova, S.O. Cross-Talk of the Glutamate and Leptin Receptor Pathways. Mol Biol 55, 441–448 (2021). https://doi.org/10.1134/S0026893321020291

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