Transient Receptor Potential Canonical (TRPC) Channels as Modulators of Migration and Invasion

Abstract

Calcium (Ca²⁺) is perhaps the most versatile signaling molecule in cells. Ca²⁺ regulates a large number of key events in cells, ranging from gene transcription, motility, and contraction, to energy production and channel gating. To accomplish all these different functions, a multitude of channels, pumps, and transporters are necessary. A group of channels participating in these processes is the transient receptor potential (TRP) family of cation channels. These channels are divided into 29 subfamilies, and are differentially expressed in man, rodents, worms, and flies. One of these subfamilies is the transient receptor potential canonical (TRPC) family of channels. This ion channel family comprises of seven isoforms, labeled TRPC1-7. In man, six functional forms are expressed (TRPC1, TRPC3-7), whereas TRPC2 is a pseudogene; thus, not functionally expressed. In this review, we will describe the importance of the TRPC channels and their interacting molecular partners in the etiology of cancer, particularly in regard to regulating migration and invasion.

Keywords: TRPC; angiogenesis; calcium; cancer; invasion; ion channels; migration; thyroid.

Figure 1

Mechanisms of Ca²⁺ signaling. Upon activation of a G-protein coupled receptor (GPCR) by an agonist, phospholipase C (PLC) is activated, which generates two second messengers; diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG is capable of activating TRPC channels in the plasma membrane and Ca²⁺ influx is triggered. IP3 diffuses through the cytoplasm and binds to IP3 receptors on the endoplasmic reticulum (ER) membranes. This binding enables ER depletion, resulting in a rapid Ca²⁺ transient. The depletion of ER is sensed by stromal interaction protein 1 (STIM1) proteins which act as sensors. STIM1 makes a complex with Orai1 channels in the plasma membrane and induces store operated Ca²⁺ entry through Orai1. Voltage-operated calcium channels open in response to a depolarization of the plasma membrane in excitable neural and muscle cells. Ca²⁺ in the cytoplasm activates ryanodine receptors and Ca²⁺ is released from the endoplasmic reticulum (ER). To avoid a Ca²⁺ flood in the cytoplasm, the pumps sarcoplasmic-endoplasmic reticulum Ca²⁺ATPase (SERCA) and plasma membrane Ca²⁺ATPase (PMCA), and the sodium calcium exchangers (NCX), are activated which export Ca²⁺ out of the cell or into the ER. The secretory pathway Ca²⁺ ATPase (SPCA) transports Ca²⁺ ions into the Golgi apparatus.

Figure 2

The human phylogenetic tree of the TRP channel superfamily. TRPC (canonical), TRPV (Vanilloid), TRPML (Mucolipin), TRPP (Polycystin), TRPM (Melastatin), TRPA (Ankyrin), and TRPN (NOMPC). TRPC2 is a pseudogene in human. TRPN is expressed in fish.

Figure 3

TRPC channel transmembrane structure and the domain organization of the subunits.