The Boston group saw TRPC5 Ca2+ channels transferring into the plasma membrane, as measured by total internal reflection microscopy, electrophysiology, and surface biotinylation, in response to several growth factors. “Instead of controlling just gating, you are controlling availability,” says Clapham.
Recruitment and activation of TRPC5 Ca2+ currents were dependent on activated Rac and production of PIP2. In combination with previous work, this suggests the following scenario: activated growth factor receptors turn on PI3K-mediated production of PIP3; PIP3 recruits an exchange factor for Rac; and active Rac binds a kinase that produces PIP2. The binding target for PIP2 may be synaptotagmin, which colocalizes with TRPC5 in vesicles.
The recruitment is transient, thus helping the cell to avoid flooding its narrow neurites with too much calcium. The calcium admitted by TRPC5 slows down neurites, possibly so they can respond to turning cues. Clapham now wants to see whether such “just in time” channel insertion events are a generalized feature of TRP channel regulation. ▪