Pathophysiological roles of TRP channels in controlling the neuronal differentiation

Abstract

Nerve growth factor (NGF) and neuronal outgrowth has been implicated in the early neuro-developmental process of the nervous system. Recently, some types of TRP channels are known to be related to neuronal differentiation and proliferation. But, it is still not well understood which types of TRP channels are involved in NGF–induced neurite outgrowth. We therefore investigated which types of TRP channels are required for the NGF-induced neuronal outgrowth using real time quantitative-PCR technique. As NGF treatment increased neurite outgrowth in length and number, its treatment similarly increased mRNA levels of TRPC1 and TRPV4 against decreasing mRNA levels of TRPC5 and TRPM2 in PC12 cells. Therefore, screening of TRP channels for neurite outgrowth led to identification of two novel (TRPM2, TRPV4) and two known (TRPC1, TRPC5) TRP channel. First candidate TRPM2 channel is a Ca2+-permeable cation channel and highly expressed in the brain. Genetic linkage studies have shown that TRPM2 is associated with bipolar disorder (BD) which is a psychotropic disorder that causes unusual shifts in mood from the manic to the depressive state, but the nature of this linkage is not known. We show that TRPM2 suppresses neurite growth. Knock-down of TRPM2 markedly increased neurite growth, whereas its upregulation had a suppressive effect. Lysophosphatidic acid (LPA), a long known inhibitory ligand of neurite growth has its action via activation of TRPM2. Surprisingly, lithium inhibited the LPA/TRPM2 pathway by blocking ADP-ribose synthesis, an endogenous ligand for TRPM2. Lithium blocked the amphetamine-induced hyperactivity, an animal model for manic state, which was completely eliminated in TRPM2-deficient mice. These results now suggest that prolonged modulation of neurite growth by TRPM2 could contribute to the pathology of BD and that TRPM2 is a downstream target of lithium, explaining the long-sought lithium pharmacology. Secondly, Peripheral neuropathies are characterized by muscle weakness and atrophy caused by the degenerations of peripheral motor and sensory nerves. Recent advances in genetics have resulted in the identification of missense mutations in the other candidate TRPV4 channel in patients with these hereditary neuropathies. Despite the importance of TRPV4 mutations in causing neuropathies, the precise role of TRPV4 in the sensory/motor neurons is unknown. We report that TRPV4 mediates neurotrophic factor-derived neuritogenesis in developing peripheral neurons. TRPV4 was found to be highly expressed in sensory and spinal motor neurons in early development as well as in the adult, and the overexpression or chemical activation of TRPV4 was found to promote neuritogenesis in sensory neurons as well as PC12 cells, whereas its knock-down and pharmacologic inhibition had the opposite effect. Neurotrophic factor–derived neuritogenesis appears to be regulated by the phospholipase A2-mediated TRPV4 pathway. These findings show that TRPV4 mediates neurotrophic factor-induced neuritogenesis in developing peripheral nerves. Because neurotrophic factors are essential for the maintenance of peripheral nerves, these findings suggest that aberrant TRPV4 activity may lead to some types of pathology of sensory and motor nerves.