Astrocytic TRPV4 Channels and Their Role in Brain Ischemia

Abstract

Transient receptor potential cation channels subfamily V member 4 (TRPV4) are non-selective cation channels expressed in different cell types of the central nervous system. These channels can be activated by diverse physical and chemical stimuli, including heat and mechanical stress. In astrocytes, they are involved in the modulation of neuronal excitability, control of blood flow, and brain edema formation. All these processes are significantly impaired in cerebral ischemia due to insufficient blood supply to the tissue, resulting in energy depletion, ionic disbalance, and excitotoxicity. The polymodal cation channel TRPV4, which mediates Ca²⁺ influx into the cell because of activation by various stimuli, is one of the potential therapeutic targets in the treatment of cerebral ischemia. However, its expression and function vary significantly between brain cell types, and therefore, the effect of its modulation in healthy tissue and pathology needs to be carefully studied and evaluated. In this review, we provide a summary of available information on TRPV4 channels and their expression in healthy and injured neural cells, with a particular focus on their role in ischemic brain injury.

Keywords: Ca2+ signaling; TRPV4; astrocytes; glia; ischemia.

Figure 2

Basic functions of astrocytic TRPV4 channels. (A) Influence of AQP4 expression in astrocyte membrane: Ca²⁺ entering the cell through TRPV4 channels binds to CaM, which subsequently activates AQP4 phosphorylation, causing its re-localization to the astrocytic membranes. (B) Cell-volume regulation: The mechanism involves cooperation between the AQP4 and TRPV4 channels. The water influx via AQP4 causes astrocyte swelling, which activates the mechanosensitive TRPV4 channel. Subsequent entry of Ca²⁺ triggers RVD via BK_Ca or VRACs. Additionally, the membrane stretch can activate PLA2, whose activity leads to the production of AA and its subsequent conversion to EETs. EETs can then further stimulate TRPV4 channels. (C) Neurovascular unit: Astrocytic mGluRs sense the extracellular glutamate released from neurons due to their increased activity. The activation of mGluRs leads to the Ca²⁺ influx and following stimulation of BK_Ca releasing K⁺ into the ECS. Extracellular K⁺ activates Kir channels in SM cells, causing vasodilation. In addition, PLA2 activation leads to the production of EETs, the opening of TRPV4 channels, and an additional Ca²⁺ increase in astrocytes. (D) Systemic blood flow control: Mechanical stimulation of TRPV4 opens the channel for Ca²⁺ entry into astrocytes and activates the interaction between TRPV4 and Cx43 hemichannels. Subsequent release of ATP into the ECS can trigger activation of astrocytic P2Y1 or neuronal purinergic receptors of brain stem sympathetic control circuits. Moreover, astrocytic P2Y1 activation enhances astrocytic excitation by stimulating the further Ca²⁺ release from internal stores. (E) Control of synaptic transmission: Activation of astrocytic TRPV4 channels by the endogenous ligand leads to excitation of neighboring astrocytes, even those that do not express TRPV4, either via gap junction mediated Ca²⁺ waves or by ATP release. These astrocytes then release glutamate, which binds to mGluRs on synaptic neurons and thus modulates the neurotransmission. Abbreviations: A, astrocyte; AA, arachidonic acid; AC, adenylyl cyclase; AQP4, aquaporin 4; ATP, adenosine triphosphate; BK_Ca, Ca²⁺-dependent K⁺ channels; CaM, calmodulin; ECS, extracellular space; EETs, eicosanoid metabolites; el, endogenous ligand; Kir, inward-rectifier potassium channel; mGluRs, metabotropic glutamate receptors; N, neuron; P2Y1, G-protein coupled purinergic receptor P2Y1; PKA, protein kinase A; PLA2, phospholipase 2; RVD, regulatory volume decrease; SM, smooth-muscle cell; VRAC, volume-regulated anion channel. The figure was inspired by schematics in publications by Kitchen et al., 2020 [120], Jo et al., 2015 [113], Turovsky et al., 2020 [133] and Shibasaki et al., 2014 [106].

Figure 1

Structure of the transient receptor potential cation channel subfamily V member 4 (TRPV4), with the main functional domains. Abbreviations: A, ankyrin; CAM, Ca²⁺/calmodulin binding site; EC, extracellular side; IC, intracellular side; TM, transmembrane domain; PRD, proline-rich domain.