Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons

Abstract

Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit changes in the cellular cytoskeleton and are involved in diverse biological processes during development, differentiation, survival and regeneration. This review summarizes the status of research regarding the expression and the role of the Rho GTPases in peripheral sensory neurons and how these small proteins are involved in development and outgrowth of sensory neurons, as well as in neuronal regeneration after injury, inflammation and pain perception. In sensory neurons, Rho GTPases are activated by various extracellular signals through membrane receptors and elicit their action through a wide range of downstream effectors, such as Rho-associated protein kinase (ROCK), phosphoinositide 3-kinase (PI3K) or mixed-lineage kinase (MLK). While RhoA is implicated in the assembly of stress fibres and focal adhesions and inhibits neuronal outgrowth through growth cone collapse, Rac1 and Cdc42 promote neuronal development, differentiation and neuroregeneration. The functions of Rho GTPases are critically important in the peripheral somatosensory system; however, their signalling interconnections and partially antagonistic actions are not yet fully understood.

Keywords: Rho GTPases; actin cytoskeleton; development; inflammation; neurite outgrowth; neuroregeneration; pain; sensory neurons.

Figure 1

The family member RhoA, effectors and activators in sensory neurons. RhoA can be activated via different receptors, such as GPCRs (G-protein coupled receptors), RTKs (receptors of the tyrosine kinase family), cytokine receptors or ion channels. RhoA activity is regulated by specific proteins: GEFs (guanine nucleotide exchange factors) which promote its active state and GAPs (GTPase activating proteins) which turn it into an inactive state. By regulating various downstream effectors, RhoA elicits changes in the actin cytoskeleton and these effects can be pharmacologically modulated by inhibitors like Clostridium botulinum C3 toxin (BoTXC3) or fasudil.

Figure 2

The sphingolipid S1P and the involvement of Rho GTPases in the outgrowth of sensory neurons. The bioactive lipid S1P elicits its action in sensory neurons depending on its local concentration and activates different members of the Rho GTPases family. High levels of S1P activate RhoA through the S1P₃ receptor and sensory neurons respond with a rapid retraction of neurites and growth cone collapse. On the other hand, S1P₁ receptor seems to be associated with Rac1 activation and consequent elongation of neuronal processes.