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Inwardly Rectifying Potassium Channel Kir4.1 As a Novel Modulator of BDNF Expression in Astrocytes

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Inwardly Rectifying Potassium Channel Kir4.1 As a Novel Modulator of BDNF Expression in Astrocytes International Journal of Molecular Sciences Review Inwardly Rectifying Potassium Channel Kir4.1 as a Novel Modulator of BDNF Expression in Astrocytes Yukihiro Ohno *, Masato Kinboshi and Saki Shimizu Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan; [email protected] (M.K.); [email protected] (S.S.) * Correspondence: [email protected]; Tel.: +81-72-690-1052; Fax: +81-72-690-1053 Received: 24 September 2018; Accepted: 22 October 2018; Published: 24 October 2018 Abstract: Brain-derived neurotrophic factor (BDNF) is a key molecule essential for neural plasticity and development, and is implicated in the pathophysiology of various central nervous system (CNS) disorders. It is now documented that BDNF is synthesized not only in neurons, but also in astrocytes which actively regulate neuronal activities by forming tripartite synapses. Inwardly rectifying potassium (Kir) channel subunit Kir4.1, which is specifically expressed in astrocytes, constructs Kir4.1 and Kir4.1/5.1 channels, and mediates the spatial potassium (K+) buffering action of astrocytes. Recent evidence illustrates that Kir4.1 channels play important roles in bringing about the actions of antidepressant drugs and modulating BDNF expression in astrocytes. Although the precise mechanisms remain to be clarified, it seems likely that inhibition (down-regulation or blockade) of astrocytic Kir4.1 channels attenuates K+ buffering, increases neuronal excitability by elevating extracellular K+ and glutamate, and facilitates BDNF expression. Conversely, activation (up-regulation or opening) of Kir4.1 channels reduces neuronal excitability by lowering extracellular K+ and glutamate, and attenuates BDNF expression. Particularly, the former pathophysiological alterations seem to be important in epileptogenesis and pain sensitization, and the latter in the pathogenesis of depressive disorders. In this article, we review the functions of Kir4.1 channels, with a focus on their regulation of spatial K+ buffering and BDNF expression in astrocytes, and discuss the role of the astrocytic Kir4.1-BDNF system in modulating CNS disorders. Keywords: astrocytes; brain-derived neurotrophic factor (BDNF); depressive disorders; epilepsy; Kir4.1 channels; pain; spatial potassium buffering 1. Introduction Astrocytes are the most abundant glial cells and play important roles in maintaining the integrity of brain functions. It is known that a single astrocyte connects 105 or more synapses, where they form “tripartite synapses” consisting of pre-synaptic nerve terminals, post-synaptic membranes of neurons and perisynaptic processes of astrocytes [1–3]. Thus, astrocytes actively regulate the excitability of neurons by regulating ion and water homeostasis at synapses, metabolizing neurotransmitters (e.g., glutamate and GABA) and secreting various neuroactive substances (e.g., gliotransmitters, neurotrophins, and cytokines) [2–6]. In addition, astrocytes are implicated in the pathogenesis of various disorders including schizophrenia, major depressive disorders, Parkinson’s disease, Alzheimer’s disease, epilepsy, and chronic pain [7–9]. Brain-derived neurotrophic factor (BDNF) is a key molecule essential for development and pathophysiology of the brain. Specifically, BDNF mediates molecular mechanisms underlying synaptic plasticity (e.g., neurite outgrowth and synaptogenesis), neural development, cell survival and active gliosis [10–13]. Elevated expression of BDNF is implicated in the pathogenesis of epilepsy and chronic pain sensitization whereas the neurotrophic property of BDNF is expected to restore neurodegenerative Int. J. Mol. Sci. 2018, 19, 3313; doi:10.3390/ijms19113313 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 2 of 19 Int. J. Mol. Sci. 2018, 19, 3313 2 of 18 and chronic pain sensitization whereas the neurotrophic property of BDNF is expected to restore disordersneurodegenerative such as Parkinson’s disorders disease such as and Parkinson’s Alzheimer’s disease disease. and EarlyAlzheimer’s studies disease. showed Early that BDNF studies was expressedshowed inthat pyramidal BDNF was neurons expressed in the in cerebralpyramidal cortex neurons and hippocampusin the cerebral [ 14cortex,15], butand ithippocampus is now known [14,15], but it is now known that astrocytes are an alternative source for BDNF expression and that astrocytes are an alternative source for BDNF expression and secretion [16,17]. Furthermore, secretion [16,17]. Furthermore, recent evidence illustrates that astrocytic BDNF expression is recent evidence illustrates that astrocytic BDNF expression is specifically modulated by the inwardly specifically modulated by the inwardly rectifying potassium (Kir) 4.1 channels, which mediate the rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium (K+) buffering function spatial potassium (K+) buffering function of astrocytes and regulate neuronal activities [9,18]. of astrocytes and regulate neuronal activities [9,18]. In this article, we review the molecular and functional characteristics of Kir4.1 channels, with a focusIn this on article,their actions we review in regulating the molecular spatial andK+ buffering functional and characteristics BDNF expression of Kir4.1 in astrocytes, channels, withand a + focusdiscuss on their the actionsrole of the in regulating astrocytic spatialKir4.1-BDNF K buffering system andin modulating BDNF expression central innervous astrocytes, system and (CNS) discuss thedisorders. role of the astrocytic Kir4.1-BDNF system in modulating central nervous system (CNS) disorders. 2. Astrocytic2. Astrocytic Kir4.1 Kir4.1 Channels Channels 2.1. Molecular Structure and Channel Properties 2.1. Molecular Structure and Channel Properties KirKir channels channels are are generally generally classifiedclassified intointo sevenseven families (Kir1 (Kir1 through through Kir7) Kir7) encompassing encompassing moremore than than 15 15 members members [[19,20].19,20]. These These can can be be categorized categorized by bytheir their characteristics characteristics into four into groups: four groups: (1) (1)G G protein-aged protein-aged channels channels (Kir3.x); (Kir3.x); (2) (2) ATP-sensitive ATP-sensitive channels channels (Kir6.x); (Kir6.x); (3) (3) clas classicalsical channels channels (Kir2.x); (Kir2.x); + andand (4) (4) K K-transport+-transport channels channels (Kir1x,(Kir1x, Kir4.x,Kir4.x, Kir5.x,Kir5.x, and Kir7.x) Kir7.x) (Figure (Figure 1).1). Among Among them, them, Kir4.1 Kir4.1 + subunitssubunits are are highly highly expressed expressed in in the the brain brain astrocytes,astrocytes, where they mediate mediate the the spatial spatial K K+ bufferingbuffering actionaction of astrocytesof astrocytes [5– 8[5–8,20–25].,20–25]. Kir4.1 Kir4.1 subunits subunits are are also also expressed expressed in retina in retina (Müller (Müller cells) cells) and kidneyand (e.g.,kidney distal (e.g., tubular distal epithelia). tubular epithelia). FigureFigure 1. 1.Molecular Molecular structure structure and and channelchannel propertiesproperties of Kir4.1 Kir4.1 channels. channels. (A (A) Classification) Classification of ofKir Kir channelschannels and and their their phylogenic phylogenic tree. tree. KirKir channelschannels consist of of 15 15 subtypes subtypes which which can can be be classified classified into into sevenseven families. families. (B )(B Kir4.1) Kir4.1 subunits subunits have have two two TM TM structures structures (TM-1 (TM-1 and and TM-2) TM-2) with with one one extracellular extracellular loop whichloopcontains which contains a signature a signature sequence: sequence: (GYG) (GYG) participating participating in ion-selective in ion-selective filtering filtering for K for+.( KC+). Kir4.1(C) subunitsKir4.1 formsubunits two typesform two of Kir4.1 types channels, of Kir4.1 the channe homo-tetramerls, the homo-tetramer of Kir4.1 (Kir4.1) of Kir4.1 and the(Kir4.1) hetero-tetramer and the of Kir4.1hetero-tetramer and Kir5.1 of (Kir4.1/5.1).Kir4.1 and Kir5.1 (D) Kir4.1 (Kir4.1/5.1). channels (D conduct) Kir4.1 largechannels inward conduct and smallerlarge inward outward and K + + 2+ + currentssmaller (sensitive outward toK Bacurrents2+), illustrating (sensitive characteristicsto Ba ), illustrating of inwardly characteristics rectifying of Kinwardly+ channels. rectifying K channels. The KCNJ10 (or Kcnj10) gene encoding the Kir4.1 subunit is located on chromosome (Chr) 1 (1q23.2)The in humans,KCNJ10 (or Chr Kcnj10 13 (13q24)) gene inencoding rats and the Chr Kir4.1 1 (1 H33)subunit in mice, is located coding on 379chromosome amino acids. (Chr) Kir4.1 1 has(1q23.2) two transmembrane in humans, Chr (TM) 13 (13q24) regions in with rats oneand extracellularChr 1 (1 H33) loop in mice, which coding contains 379 aamino signature acids. sequence: Kir4.1 has two transmembrane (TM) regions with one extracellular loop which contains a signature (GYG) participating in ion-selective filtering for K+ (Figure1)[ 5,6,8,20]. Kir4.1 channels are constructed sequence: (GYG) participating in ion-selective filtering for K+ (Figure 1) [5,6,8,20]. Kir4.1 channels are as a homo-tetramer of Kir4.1 subunits. Kir4.1 subunits also form Kir4.1/5.1 channels (hetero-tetramer of Kir4.1 and Kir5.1 subunits) with another subunit Kir5.1, Kir4.1, and Kir4.1/5.1 channels allow large Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 3 of 19 Int.constructed J. Mol. Sci. 2018 as, 19 a, 3313homo-tetramer of Kir4.1 subunits. Kir4.1 subunits also form Kir4.1/5.1 channels3
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