TRPC3/6/7: Topical aspects of biophysics and pathophysiology

Abstract

Nonselective and lipid-regulated cation channels formed by TRPC3, TRPC6 and TRPC7 have recently obtained attention in view their potential pathophysiological impact. It appears as a particular challenge to understand the molecular basis of TRPC3/6/7-related diseases in order to further delineate their value as therapeutic targets. The multifunctional nature of these channel proteins, based on a complex, versatile heteromerization potential along with highly promiscuous gating and mixed cation permeation properties, make these channels pivotal players in cellular signaling networks. Here we summarize newsworthy aspects of TRPC3/6/7 physiology and pathophysiology that open the view on novel therapeutic strategies based on these TRPCs as target structures.

Calcium Sensing Receptor Modulates Extracellular Calcium Entry and Proliferation via TRPC3/6 Channels in Cultured Human Mesangial Cells

“…As shown in Fig. 4A and 4B, pretreatment with SKF96365 (50 µM) or 2-APB (100 µM), nonselective TRPC channel blockers [19], significantly inhibited the 5 mM [Ca 2+ ] o - and 3 mM spermine-induced [Ca 2+ ] i increase, whereas pretreatment with efonidipine (10 µM, a voltage-gated calcium blocker) or SN-6 (10 µM, an specific inhibitor of NCX) had no apparent effect (Fig. 4C and 4D).…”

“…In MCs, as in other cell types, TRPC3 channels and TRPC6 channels are considered to be ROCs [16], [19], whereas TRPC1 channels and TRPC4 channels are SOCs [26]. Given that a functional hallmark of ROCs is that they can be directly activated by DAG without depleting intracellular stores, CaSR agonists may be able to induce the activation of ROCs because PLC-mediated DAG production following CaSR stimulation has been demonstrated in a number of studies [1], [9], [27], [28].…”

PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes

“…TRPC channels are expected to contribute divergently to Ca 2+ signaling in nonexcitable and in excitable cells, which provide a certain repertoire of voltage-dependent Ca 2+ transport systems. TRPC3 is a lipid-regulated member of the TRPC subfamily and a potential player in cardiac pathophysiology (9). For homomeric TRPC3 channels, a Ca 2+ /Na + permeability ratio of ≈1.6 was determined (10) and functional crosstalk of TRPC3 channels with cardiac voltage-gated Ca 2+ channels and NCX1 has been suggested (7,11).…”

Transient receptor potential channelopathies

“…Although mutations in TRPC channel genes have been linked to cardiovascular diseases [30,39,75,106,136,165,171], pulmonary diseases [88], inflammation [16], cancer [43], skin diseases [111], neurological diseases [36], (diabetic) kidney diseases [166], and proliferative diseases via dysregulation of the cell cycle [120], the only TRPCrelated channelopathy described so far is focal and segmental glomerulosclerosis (FSGS). FSGS is functionally characterized by proteinuria and progressive decline in renal function of the late onset type.…”