How CBD connects to a promising cellular target

The transient receptor potential vanilloid 2 (TRPV2) channel is a Ca2+-permeable non-selective cation channel widely expressed in immune cells, cardiomyocytes, neurons, and various cancers. It participates in diverse physiological and pathological processes, including neuronal differentiation, mechanosensation, immune responses, and oncogenesis. Despite its broad significance, the mechanisms governing TRPV2 activation and its therapeutic potential remain incompletely understood. Recent high-resolution cryo-EM studies have revealed its tetrameric architecture and gating-associated conformational changes. Functional studies have identified several chemical agonists, such as 2-APB and CBD, but their lack of specificity highlights the need for endogenous modulators. Key discoveries include ROS-mediated sensitization via methionine oxidation, pH-dependent gating by weak acids, and cholesterol binding that stabilizes distinct channel states. Furthermore, dynamic post-translational modifications (PTMs), including phosphorylation, ubiquitination, and S-palmitoylation, precisely control the TRPV2 lifecycle, from biosynthesis and membrane trafficking to gating and degradation. These PTMs precisely control the entire TRPV2 lifecycle, from biosynthesis and membrane trafficking to gating, complex assembly, and degradation, thereby tuning TRPV2 sensitivity and function. This review synthesizes the structural basis and intricate endogenous regulatory network of TRPV2, emphasizing its evolution from a simple thermosensor to a complex integrator of cellular signals. Understanding these mechanisms is pivotal for developing novel, precise therapeutic strategies targeting TRPV2 in neurological, cardiovascular, and immune diseases.