Trpc5, the human canonical transient receptor potential channel 5, is a Ca(2+)-permeable cation channel. It is predominantly expressed in the CNS, including regions like the hippocampus, cerebellum, and also in the periphery such as the kidney and cardiovascular system. TRPC5 channels are mainly activated by Gq and phospholipase C-or Gi-coupled receptors, and can also gate in a store-dependent manner with partner proteins. They participate in various Ca(2+) signalling and electrogenesis pathways, and are crucial for functions from neurotransmission to axon guidance and vascular smooth muscle cell activities [1].

Studies using Trpc5 gene knockouts have started to uncover its roles. In mice lacking Trpc5, insulin-evoked hypoglycemia is severely aggravated as the lack of Trpc5 in adrenal chromaffin cells prevents proper adrenaline rise in plasma, indicating its role in the adrenaline-mediated counter-regulation of hypoglycemia [3]. Also, investigations with global and conditional deficient mice have revealed the involvement of Trpc5 in metabolic diseases, energy balance, thermosensation, and conditions like osteoarthritis, rheumatoid arthritis, and inflammatory pain [2].

In conclusion, Trpc5 is essential for multiple biological functions, especially in Ca(2+)-related signalling pathways. Model-based research, particularly through Trpc5 KO/CKO mouse models, has provided insights into its roles in diseases such as hypoglycemia-associated disorders, metabolic diseases, and inflammatory pain conditions, highlighting its potential as a therapeutic target in these disease areas.