Transient receptor potential (TRP) cation channels are cellular sensors for a wide spectrum of physical and chemical stimuli, and mammalian species possess 28 TRP channels (Zheng, 2013). All TRP channels have six transmembrane segments (S1–S6), such as voltage-gated potassium channels; both the N and C termini are intracellularly located (Benemei et al., 2015). TRPV1 is one of the TRP cation channels that can be activated by heat (Zheng, 2013). The TPRV1 structure can be divided into three parts: the N- and C-termini in cells, and the six transmembrane segments with pore loop region formed between S5 and S6 (Juárez-Contreras et al., 2020). The N-terminus of TRPV1 contains calmodulin and ATP binding sites, which modulate the activation of the channel (Cao et al., 2013; Lee and Zheng, 2015). Sites on the N-terminus are capable of phosphorylation by protein kinases with S116 proposed to be the most critical phosphorylation site for PKA-dependent reduction of desensitization (Mohapatra and Nau, 2003). A linker domain connects the N-terminus to the transmembrane region via the pre-helical segment (pre-S1) and connects TPRV1 subunits together (Liao et al., 2013).

The C-terminus contains protein kinase C (PKC) phosphorylation sites and sites for binding calmodulin and phosphatidylinositol-4,5-bisphosphate (PIP2), which can modulate the activation of the C-terminus (Jara-Oseguera et al., 2008). In addition, the C-terminus region of TRPV1 as a physiologically important Ca²⁺- CaM-binding site is implicated in TRPV1 desensitization (Lau et al., 2012). Furthermore, the thermal sensing domain is localized within the C-terminus (Brauchi et al., 2007).

The transmembrane region of the TRPV1 subunit comprises six helical segments (S1–S6), in which S1–S4 contribute to the voltage-sensing domain, and S5–S6 contribute to the pore-forming domain (Liao et al., 2013). S1–S4 are connected to S5 and S6 through the connecting segment and act as a foundation, which allows the linker segment to move, contributing to pore opening and TRPV1 activation. The transmembrane region also contains binding sites for several ligands (Cao et al., 2013).

TPRV1 is highly permeable to Ca²⁺ by cloning the genes expressed in dorsal root ganglion and overexpressed in human embryonic kidney cells in 1997 (Caterina et al., 1997). TRPV1 is highly expressed in brain stem, midbrain, hypothalamus, and limbic system in central tissues and widely expressed in heart, fat, and skeletal muscle in peripheral tissues (Edwards, 2014). Myofibers from skeletal muscles are generally categorized into glycolytic type II (fast twitch muscle fiber) and oxidative type I (slow twitch muscle fiber); there are more TRPV1 in the oxidative type I than in the glycolytic type II (Luo et al., 2012). The intracellular localization of TRPV1 is different between tissues. For example, TRPV1 is present in both the SR and mitochondrial outer membrane in cardiomyocytes (Randhawa and Jaggi, 2015; Juárez-Contreras et al., 2020), whereas TRPV1 in skeletal muscle cells is localized on the SR (Xin et al., 2005). TRPV1 is enriched in longitudinal SR but not in the mixture of longitudinal SR and terminal cisternae, which is drawn from Western blot results from protein samples prepared by sucrose step gradient centrifuge (Lotteau et al., 2013). Moreover, immunofluorescence observation confirmed the localization of TRPV1 on the SR membrane rather than on the sarcolemma (Lotteau et al., 2013).

Long-term activation of TRPV1 promotes mitochondrial biogenesis. Ca²⁺ is a general intracellular messenger and plays an important role in various physiological and biochemical reactions of cells (Chin, 2010). Maintaining intracellular Ca²⁺ homeostasis is essential for cell function. The expression of TRPV1 and cytosolic Ca²⁺ concentration in skeletal muscle cells increased in mice fed with capsaicin for 4 months, which increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a master regulator in promoting mitochondrial biogenesis, and enhanced aerobic endurance capacity (Luo et al., 2012). The sustained activation of TRPV1 by injecting 10 μM capsaicin twice a day for 13 days promoted the release of SR Ca²⁺ and induced the mitochondrial biogenesis of skeletal muscle in mice (Ito et al., 2013).

Long-term activation of TRPV1 may promote mitochondrial biogenesis through the Ca²⁺-CaMKII-p38 MAPK-PGC-1α signaling axis (Figure 1). The sustained activation of TRPV1 by feeding mice with diet containing 0.01% capsaicin for 16 weeks upregulated PGC-1α expression and promoted mitochondrial biogenesis in kidney cells, which improved glomerular mitochondrial function (Wei et al., 2020). Luo et al. (Luo et al., 2012) subjected C57BL/6 J wild-type mice and TRPV1 knock-out mice to the dietary intervention of 0.01% capsaicin for 4 months. The results showed that sustained activation of TRPV1 by dietary capsaicin upregulated PGC-1α and increased mitochondrial content and ADP-stimulated respiratory functions of skeletal muscle in C57BL/6 J wild-type mice but not in TRPV1 knockout mice. Moreover, high TRPV1 expression in TRPV1-transgenic mice increased PGC-1α expression, oxidative fiber ratio, and exercise endurance. Therefore, chronic activation of TRPV1 in skeletal muscle can increase cytosolic Ca²⁺ concentration and PGC-1α contents, which can promote mitochondrial biogenesis and aerobic endurance capacity. In addition, studies have found that mitochondrial biogenesis is suppressed after TRPV1 inhibition. In septic mice, 30 mg/kg TRPA1 antagonist A-967079 inhibited the expression of TRPV1 in kidney cells; 1 week later, PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased by 68.3 and 53.15%, respectively, indicating that inhibition of TRPV1 reduced mitochondrial biogenesis signals (Zhu et al., 2018). PGC-1α in muscle is an essential regulator of mitochondrial biogenesis. High expression of PGC-1α in skeletal muscle of transgenic mice resulted in the increase of mitochondrial biogenesis and oxidative muscle fibers (Rowe et al., 2013), whereas the deletion of PGC-1α and PGC-1β in muscle led to a significant decrease in mitochondrial respiration, electron transport chain (ETC)/OXPHOS gene expression, and aerobic exercise performance (Terada et al., 2005). The above evidence showed that TRPV1 activation for a long period can promote mitochondrial biogenesis by upregulating PGC-1α expression in a Ca²⁺-dependent manner.

TRPV1-mediated Ca²⁺ release may induce PGC-1α expression through the activation of CaMKII. The activation of CaMKII enhances the phosphorylation level of p38 MAPK, which then initiates the transcription of PGC-1α, thereby promoting mitochondrial biogenesis (Akimoto et al., 2005). Kidney cells isolated from mice fed with 0.01% capsaicin for 16 weeks exhibited increased expression of TRPV1, CaMKII, and the phosphorylation levels of CaMKII (Wei et al., 2020). The activation effect of TRPV1 on 5′ AMP-activated protein kinase (AMPK) was abolished by knocking down CaMKII, but the inhibition of AMPK did not affect CaMKII phosphorylation by TRPV1 (Wei et al., 2020). These results indicated the presence of a TRPV1-Ca²⁺-CaMKII signaling axis. Therefore, chronic activation of TRPV1 may promote mitochondrial biogenesis through the Ca²⁺-CaMKII-p38 MAPK-PGC-1α signaling axis.

Ca²⁺ concentration is one of the key regulators of TRPV1 desensitization because the persistent exposure of TRPV1 to Ca²⁺ stimulation can attenuate its responses (Zhao and Tsang, 2017). High intracellular Ca²⁺ concentration reduces TRPV1 activity through negative feedback and dynamically adjusts intracellular Ca²⁺ concentration (Shuba, 2020). Dephosphorylation by Ca²⁺-dependent phosphatase calcineurin is also involved in regulating TRPV1 desensitization (Bevan et al., 2014). Phosphorylation mediated by CaMKII, PKA, and PKC at several consensus sites has been reported to decrease Ca²⁺-mediated desensitization of TRPV1 (Vyklický et al., 2008). Therefore, TRPV1-mediated CaMKII activation may serve as positive feedback to amplify the signal. The biological significance of calmodulin-mediated reduction of TRPV1 activity and CaMKII-mediated reduction of TRPV1 desensitization is to regulate repeated stimulations of TRPV1 and maintain intracellular Ca²⁺ concentration.