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The Calcium/Calmodulin-Dependent Kinases II and IV As Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders

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The Calcium/Calmodulin-Dependent Kinases II and IV As Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders International Journal of Molecular Sciences Review The Calcium/Calmodulin-Dependent Kinases II and IV as Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders Kinga Sałaciak 1, Aleksandra Koszałka 1, Elzbieta˙ Zmudzka˙ 2 and Karolina Pytka 1,* 1 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland; [email protected] (K.S.); [email protected] (A.K.) 2 Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland; [email protected] * Correspondence: [email protected] Abstract: CaMKII and CaMKIV are calcium/calmodulin-dependent kinases playing a rudimentary role in many regulatory processes in the organism. These kinases attract increasing interest due to their involvement primarily in memory and plasticity and various cellular functions. Although CaMKII and CaMKIV are mostly recognized as the important cogs in a memory machine, little is known about their effect on mood and role in neuropsychiatric diseases etiology. Here, we aimed to review the structure and functions of CaMKII and CaMKIV, as well as how these kinases modulate the animals’ behavior to promote antidepressant-like, anxiolytic-like, and procognitive effects. The review will help in the understanding of the roles of the above kinases in the selected neurodegenerative and neuropsychiatric disorders, and this knowledge can be used in future drug design. Citation: Sałaciak, K.; Koszałka, A.; Zmudzka,˙ E.; Pytka, K. The Keywords: CaMKII; CaMKIV; memory; depression; anxiety; animal studies Calcium/Calmodulin-Dependent Kinases II and IV as Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders. Int. J. 1. Introduction Mol. Sci. 2021, 22, 4307. https:// Calcium (Ca2+) controls virtually all aspects of cell life [1]. Cytoplasmic Ca2+ concen- doi.org/10.3390/ijms22094307 trations rise in response to either the activation of Ca2+-channels in the plasma membrane or by its release from intracellular stores (endoplasmic reticulum, ER). However, to fulfill Academic Editor: Naruhiko Sahara its role, the Ca2+ signal has to be suitably processed. The process is performed by sen- sor proteins, such as calmodulin (CaM), which can specifically complex Ca2+. CaM is a Received: 22 March 2021 major Ca2+-binding protein in the central nervous system. The molecule has four similar Accepted: 17 April 2021 2+ 2+ Published: 21 April 2021 domains, each containing one Ca -binding site. After binding to CaM, Ca alters its conformation, and the resulting CaM–Ca2+ complex can interact with target proteins and 2+ Publisher’s Note: MDPI stays neutral modulate their activity. The major CaM target proteins are Ca /CaM-dependent kinases with regard to jurisdictional claims in (CaMKs), which contribute to many neuronal regulatory pathways, from synaptic plasticity published maps and institutional affil- to gene transcription (Figure1). 2+ iations. CaMKs are a large family of protein kinases that act by Ca /calmodulin binding and subsequent protein phosphorylation. There are four enzymatically active multifunctional members of CaMKs: CaMKI, CaMKII, CaMKK, and CaMKIV, whose activation affects many downstream targets [5]. Moreover, there are also substrate-specific CaMKs, such as CaMKIII (identified as eukaryotic elongation factor-2 (eEF2) kinase) with one signaling Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. pathway according to the cell or tissue, where they are expressed [6]. Calmodulin kinases This article is an open access article play a crucial role in brain functioning, including synaptic plasticity, neuronal transmission, distributed under the terms and circuit development, and cognition. Among these kinases, CaMKII and CaMKIV are conditions of the Creative Commons currently the most investigated for neuronal functioning [7] (Table1). Both CaMKII and Attribution (CC BY) license (https:// CaMKIV belong to the serine/threonine protein kinase family and are regulated by the 2+ creativecommons.org/licenses/by/ Ca /CaM complex. In general, they are arranged into small and large lobe, creating an 4.0/). ATP-binding site and a hinge polypeptide [8]. Although closely related, multifunctional Int. J. Mol. Sci. 2021, 22, 4307. https://doi.org/10.3390/ijms22094307 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4307 2 of 32 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 32 CaMKII and CaMKIV appear to show different structures and models of regulating the autoinhibitory mechanism associated with the activation [9]. Voltage-sensitive Ligand-gated G-protein Ca2+ channel Ca2+ channel receptor α Υ β 2+ Ca IP3 IP3R CaM RyR CaMKK Endoplasmic reticulum CaMKII CaMKIV Presynaptic part: Postsynaptic part: Nucleus Regulation of multiple proteins activity through - regulation of activity of multiple proteins - phosphorylation of substrates involved phosphorylation: through phosphorylation in gene transcription (e.g., CREB) - neurotransmitter synthesis - neurotransmitter vesicle availability and release (e.g.,synapsin I phosphorylation) - cytoskeletal regulating proteins (e.g., MAP2) - membrane channels (e.g., calcium channels) - other enzymes (e.g., tyrosine hydroxlyase). FigureFigure 1. The 1. Thecalcium/ calcium/calmodulin-dependentcalmodulin-dependent kinase kinase (CaMK) (CaMK) II and IICaMKIV and CaMKIV activation activation cascades cascades and function and function in the cen- in the 2+ tralcentral nervous nervous system system(based on (based [2–4] on). Cytoplasmic [2–4]). Cytoplasmic Ca concentrations Ca2+ concentrations rise in response rise in to response either the to activation either the of activation voltage- of sensitive Ca2+-channels, ligand-gated ionotropic channels, or G-protein-coupled receptors in the plasma membrane or by voltage-sensitive Ca2+-channels, ligand-gated ionotropic channels, or G-protein-coupled receptors in the plasma membrane its release from endoplasmic reticulum via IP3R or RyR. Next, CaM binds Ca2+ ions and either activates CaMKII directly or by its release from endoplasmic reticulum via IP R or RyR. Next, CaM binds Ca2+ ions and either activates CaMKII or activates CaMKK, which in turn phosphorylates CaMKIV.3 CaM—calmodulin, CaMKK—CaMK kinase, CREB—cAMP directly or activates CaMKK, which in turn phosphorylates CaMKIV. CaM—calmodulin, CaMKK—CaMK kinase, CREB— response element-binding protein, IP3—inositol trisphosphate, IP3R—IP3 receptor, MAP2—microtubule-associated pro- teincAMP 2, RyR response—ryanodine element-binding receptors. protein, IP3—inositol trisphosphate, IP3R—IP3 receptor, MAP2—microtubule-associated protein 2, RyR—ryanodine receptors. CaMKs are a large family of protein kinases that act by Ca2+/calmodulin binding and subsequentThis protein review phosphorylation. aimed to systematize There the are current four enzymatically knowledge from active preclinical multifunctional studies on membersthe role of of CaMKs: CaMKII andCaMKI, CaMKIV CaMKII, in the CaMKK, antidepressant- and CaMKIV, and anxiolytic-like whose activation effects, affects as well as manymemory downstream formation targets and its[5]. impairment. Moreover, there The revieware also helps substrate in the-specific understanding CaMKs, ofsuch the as roles CaMKIIIof the above(identified kinases as ineukaryotic the selected elongation neurodegenerative factor-2 (eEF2) and neuropsychiatrickinase) with one disorders signaling and use this knowledge in future drug design. pathway according to the cell or tissue, where they are expressed [6]. Calmodulin kinases play a crucial role in brain functioning, including synaptic plasticity, neuronal transmis- sion, circuit development, and cognition. Among these kinases, CaMKII and CaMKIV are currently the most investigated for neuronal functioning [7] (Table 1). Both CaMKII and CaMKIV belong to the serine/threonine protein kinase family and are regulated by the Ca2+/CaM complex. In general, they are arranged into small and large lobe, creating an ATP-binding site and a hinge polypeptide [8]. Although closely related, multifunctional CaMKII and CaMKIV appear to show different structures and models of regulating the autoinhibitory mechanism associated with the activation [9]. Int. J. Mol. Sci. 2021, 22, 4307 3 of 32 Table 1. Comparison of calcium/calmodulin-dependent kinases (CaMK) II and IV, considering brain regions, cell types, functions, and disease-like states in rodents associated with dysfunctions of kinases. CaMKII CaMKIV prefrontal cortex [10,11], hippocampus [12,13], Brain regions hippocampus [17], nucleus accumbens [18] amygdala [14], lateral habenula [15,16] isoforms α and β: brain neurons; nervous tissue (mostly in cerebellum’s granular Cell types isoforms γ and δ: present in every examined cells [21]), thymus (especially T-lymphocytes), tissue [19,20] spleen, and testis [22] regulation of various cellular functions by regulation of various cellular functions by phosphorylating a wide range of substrates, e.g., phosphorylating a wide range of substrates, e.g., Function controlling transcription factors such as CREB, regulation of immune system [23–25], cardiac ATF-1, SRF [30–33], blood pressure [34], immune function [26–28], pain [29] system [35–37], microtubule dynamics [38] abnormal phosphorylation—Angelman Examples of syndrome [39], β isoform overexpression and increased activity—various dysfunction and overexpression—depressive-like symptoms [15], β types of cancer [42], knockout or associated
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