TRP Channels Regulation of Rho GTPases in Brain Context and Diseases

Abstract

Neurological and neuropsychiatric disorders are mediated by several pathophysiological mechanisms, including developmental and degenerative abnormalities caused primarily by disturbances in cell migration, structural plasticity of the synapse, and blood-vessel barrier function. In this context, critical pathways involved in the pathogenesis of these diseases are related to structural, scaffolding, and enzymatic activity-bearing proteins, which participate in Ca²⁺- and Ras Homologs (Rho) GTPases-mediated signaling. Rho GTPases are GDP/GTP binding proteins that regulate the cytoskeletal structure, cellular protrusion, and migration. These proteins cycle between GTP-bound (active) and GDP-bound (inactive) states due to their intrinsic GTPase activity and their dynamic regulation by GEFs, GAPs, and GDIs. One of the most important upstream inputs that modulate Rho GTPases activity is Ca²⁺ signaling, positioning ion channels as pivotal molecular entities for Rho GTPases regulation. Multiple non-selective cationic channels belonging to the Transient Receptor Potential (TRP) family participate in cytoskeletal-dependent processes through Ca²⁺-mediated modulation of Rho GTPases. Moreover, these ion channels have a role in several neuropathological events such as neuronal cell death, brain tumor progression and strokes. Although Rho GTPases-dependent pathways have been extensively studied, how they converge with TRP channels in the development or progression of neuropathologies is poorly understood. Herein, we review recent evidence and insights that link TRP channels activity to downstream Rho GTPase signaling or modulation. Moreover, using the TRIP database, we establish associations between possible mediators of Rho GTPase signaling with TRP ion channels. As such, we propose mechanisms that might explain the TRP-dependent modulation of Rho GTPases as possible pathways participating in the emergence or maintenance of neuropathological conditions.

Keywords: GAPs; GEFs; Rho GTPases; TRP channels; TRP interactome; actin cytoskeleton.

FIGURE 1

Cyclic Rho GTPase modulation, functions, and TRP channel-mediated regulation hypothesis. Rho GTPases cycle between an active form bound to GTP (blue arrows) and an inactive form that is attached to GDP (red arrows). Binding to guanosine nucleotide is induced by GEF proteins. GAP proteins promote GTPase activity, and GDI proteins preclude GDP exchange to GTP. The active state of Rho GTPase promotes the rearrangement of the actin cytoskeleton by the modulation of several effectors. The actin cytoskeleton mediates multiple processes depending on the cell types. In neurons, axon outgrowth and dendritic spine dynamics regulation. In brain vasculature, Rho GTPases regulate endothelial permeability and vascular tone regulation. Rho GTPases regulates migration in glial cells. TRP channels-mediated Ca²⁺ influx regulates signal transductors/modulators, leading to changes in GAP, GEF, or GDI activity, thus promoting Rho GTPases activation/inactivation and actin cytoskeleton regulation.

FIGURE 2

Map of curated TRP ion channel interactors associated with Rho GTPases pathways. Data obtained from the TRIP database showing interactors of TRPC3, TRPC5, TRPC6, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, TRPM8, and TRPML1. TRP channels members are grouped and color-coded by families.

FIGURE 3

Possible mechanisms of Rho GTPases modulation by TRP channels. Glia and Neuroblastoma: TRPC6 might modulate RhoA in glial cells, thus regulating cell migration. TRPM7 participates in neuroblastoma invasion. Vasculature: TRPV4 and TRPM8 display the opposite effect over RhoA. Both channels modulate vasculature tone. TRPV4 promotes endothelial dilation in a RhoA-dependent fashion. Axon cone: TRPML1-dependent regulation of protein trafficking via modulation of Rac1/Cdc42 might occur. TRPV1 promotes RhoA activity and modulates axonal growth. TRPV2 might have an inhibitory role of RhoA. Dendrites and spines: TRPM4, TRPC3, TRPC6, and TRPC5 might induce Rac1 activity, leading to dendritic spines formation. Under ischemic conditions, these channels might have a Rac1-dependent role in ROS production, leading to neuronal cell death. TRPM7 and TRPC5 are proposed to regulate RhoA, favoring the retraction of dendritic spines or axonal growth.