Targeting TRPC channels for control of arthritis-induced bone erosion.

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels.

TRPC3: how current mechanistic understanding provides a basis for therapeutic targeting.

Introduction: Intensive and detailed investigations of the molecular function and cellular role of mammalian transient receptor potential canonical (TRPC) channels started back in the early 90 of the past century. Initial TRPC research was fueled by high hopes to resolve fundamental questions of cellular Ca signaling. To date, we have learned important lessons in TRPC channel biology and biophysics, while little progress has been made in terms of therapeutic concepts.

TRPC1: The housekeeper of the hippocampus.

The non-selective cation channel TRPC1 is highly expressed in the brain. Recent research shows that neuronal TRPC1 forms heteromeric complexes with TRPC4 and TRPC5, with a small portion existing as homotetramers, primarily in the ER. Given that most studies have focused on the role of heteromeric TRPC1/4/5 complexes, it is crucial to investigate the specific role of homomeric TRPC1 in maintaining brain homeostasis.

PIP modulates TRPC3 activity via TRP helix and S4-S5 linker.

The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices.

Bidirectional Allosteric Coupling between PIP Binding and the Pore of the Oncochannel TRPV6.

The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting.