TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the developing brain

Abstract

Intracellular Ca(2+) signal is a key regulator of axonal growth during brain development. As transient receptor potential (TRP) channels are permeable to Ca(2+) and mediate numerous brain functions, it is conceivable that many TRP channels would regulate neuronal differentiation. We therefore screened TRP channels that are involved in the regulation of neurite growth. Among the TRP channels, the Trpm2 level was inversely associated with neurite growth. TRPM2 was highly expressed in embryonic brain. Pharmacological perturbation or knockdown of TRPM2 markedly increased the axonal growth, whereas its overexpression inhibited the axonal growth. Addition of ADP ribose, an endogenous activator of TRPM2, to PC12 cells significantly repressed the axonal growth. TRPM2 was actively involved in the neuronal retraction induced by cerebrospinal fluid-rich lysophosphatidic acid (LPA). More importantly, neurons isolated from the brain of Trpm2-deficient mice have significantly longer neurites with a greater number of spines than those obtained from the brain of wild-type mice. Therefore, we conclude that TRPM2 mediates the LPA-induced suppression of axonal growth, which provides a long-sought mechanism underlying the effect of LPA on neuronal development.

Lysophosphatidic Acid Signaling in the Nervous System

“…Neurite retraction (Hecht et al, 1996), an important response to chemical gradients, can be mediated by LPA via the ROCK pathway (Tigyi et al, 1996). More recently, transient receptor potential channel, subfamily M, member 2 (TRPM2) was reported to mediate LPA-induced neurite retraction in the developing brain (Jang et al, 2014). Finally, neurite branching, an important process for neuronal network formation, was induced through the introduction of LPA 3 and the addition of LPA into hippocampal cell cultures (Furuta et al, 2012).…”

Understanding Thermosensitive Transient Receptor Potential Channels as Versatile Polymodal Cellular Sensors

“…Recently, TRPM2 was shown to play an important role in neuritogenesis during embryonic brain development. 30 In this process, axonal growth and retraction must be properly balanced as the brain is shaped.…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…It has been well evidenced that activation of LPARs can stimulate phospholipase C (PLC), thus leading to a temporary release of calcium from the ER. Furthermore, it has also been validated that LPA can directly induce Ca 2+ influx from the extracellular fluid (Jang et al, 2014). Fukushima et al (2002a) TABLE 1 | Signaling mechanism, G-protein-coupled lysophospholipids receptors, and their identified physiological and pathological functions.…”