- Transient Receptor Potential Canonical (TRPC) channels are a subfamily of the larger transient receptor potential (TRP) channel superfamily, playing key roles in calcium signaling and cellular homeostasis.
- TRPC channels are primarily activated through receptor-operated mechanisms, especially those involving G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). These pathways typically stimulate phospholipase C (PLC), leading to the production of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃), which together initiate TRPC activation.
- Importantly, TRPC channels are non-selective cation channels that allow the influx of calcium (Ca²⁺) and sodium (Na⁺), contributing to a wide variety of physiological responses such as smooth muscle contraction, neuronal excitability, and cellular proliferation.
- The TRPC subfamily consists of seven members in mammals: TRPC1 through TRPC7. These channels are often grouped into functional clusters based on sequence homology and mode of activation: TRPC1, TRPC4, and TRPC5 form one group; TRPC3, TRPC6, and TRPC7 form another; and TRPC2 is a pseudogene in humans but is functional in some other mammals and is involved in pheromone signaling. TRPC1 is considered a fundamental regulatory component, often forming heteromeric complexes with other TRPC members. TRPC3/6/7 channels are directly activated by DAG in a PLC-dependent but IP₃-independent manner, whereas TRPC4/5 channels are generally more sensitive to receptor-operated activation and may involve indirect mechanisms for gating.
- Structurally, TRPC channels possess the characteristic six transmembrane domains (S1–S6) common to all TRP channels, with a pore-forming region between S5 and S6. Their cytoplasmic N- and C-terminal regions contain regulatory motifs such as calmodulin-binding domains, ankyrin repeats, and sites for phosphorylation, allowing for dynamic regulation by intracellular signals. TRPCs can form both homomeric and heteromeric channel complexes, leading to diverse functional profiles depending on the specific subunits involved and the tissue in which they are expressed.
- Physiologically, TRPC channels are crucial in several organ systems. In the cardiovascular system, they contribute to the regulation of vascular tone and cardiac hypertrophy. In neurons, they are involved in synaptic plasticity and receptor-mediated calcium entry, influencing learning, memory, and sensory processing. TRPCs are also expressed in kidney, immune, and reproductive tissues, where they influence cell signaling, migration, and differentiation. Dysfunction or aberrant expression of TRPC channels has been associated with various pathological conditions, including hypertension, cardiac remodeling, neurodegeneration, and cancer, making them attractive targets for therapeutic development.
