Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca 2+ 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 ²⁺ signals in breast and prostate cancer-derived cells. Capsaicin (CAPS; 50μM) evoked intracellular Ca ²⁺ oscillations and/or intercellular Ca ²⁺ 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 ²⁺ ions. Concomitant oscillations of the mitochondrial matrix Ca ²⁺ concentration resulted in mitochondria energization evidenced by increased ATP production. CAPS-induced Ca ²⁺ 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 ²⁺ oscillations; rather it resulted in low-magnitude, long-lasting elevations of the cytosolic Ca ²⁺ concentration. This indicates that sole TRPV1 activation is not sufficient to generate Ca ²⁺ 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 ²⁺ signal.
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