Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca oscillations.

Sensory neuron subpopulations as well as breast and prostate cancer cells express functional transient receptor potential vanilloid type 1 (TRPV1) ion channels; however little is known how TRPV1 activation leads to biological responses. Agonist-induced activation of TRPV1 resulted in specific spatiotemporal patterns of cytoplasmic Ca signals in breast and prostate cancer-derived cells. Capsaicin (CAPS; 50μM) evoked intracellular Ca oscillations and/or intercellular Ca waves in all cell lines. As evidenced in prostate cancer Du 145 cells, oscillations were largely dependent on the expression of functional TRPV1 channels in the plasma membrane, phospholipase C activation and on the presence of extracellular Ca ions. Concomitant oscillations of the mitochondrial matrix Ca concentration resulted in mitochondria energization evidenced by increased ATP production. CAPS-induced Ca oscillations also occurred in a subset of sensory neurons, yet already at lower CAPS concentrations (1μM). Stimulation of ectopically expressed TRPV1 channels in CAPS-insensitive NIH-3T3 cells didn't provoke CAPS-triggered Ca oscillations; rather it resulted in low-magnitude, long-lasting elevations of the cytosolic Ca concentration. This indicates that sole TRPV1 activation is not sufficient to generate Ca oscillations. Instead the initial TRPV1-mediated signal leads to the activation of the inositol phospholipid pathway. This in turn suffices to generate a biologically relevant frequency-modulated Ca signal.