TRPC channels in nerve guidance. An extracellular gradient of guidance cue (from left upper corner) triggers local [Ca²⁺]_i elevation, establishing a [Ca²⁺]_i gradient across the growth cone. The graded calcium signal causes imbalanced polymerization/stablization of actin and microtubule elements and polarized transport of membrane vesicles (circle) to drive the growth cone extending toward the higher Ca²⁺ side. Calcium elevation is achieved by the binding of the guidance cue (e.g., BDNF or netrin) with its receptor (TrkB or DCC) on the surface of the growth cone, leading to the activation of phospholipase-γ (PLC-γ), which catalyzes the production of IP₃. The activation of IP₃R at the endoplasmic reticulum triggers Ca²⁺ release from internal stores. This process is coupled to the mobilization of TRPC channels in the plasma membrane through unknown mechanisms, resulting in Ca²⁺ influx. The membrane depolarization triggered by the opening of TRPC channels may activate VDCCs, which bring in additional Ca²⁺ influx. TRP channels at the soma and other parts of the migrating neurons are supposed to act as sensors for temperature and mechanical forces.