As a component of the store-operated Ca²⁺ (SOC) channels, TRPC channels, primarily located in the plasma membrane, can be activated by G protein-coupled receptors (GPRs), protein kinases, or mechanical stimulation to form non-selective Ca²⁺ osmotic channels, mediating Ca²⁺ and some monovalent ions influx, and promoting cell depolarization (Chen et al., 2020; Lopez et al., 2020). In the pancreas, TRPC1, TRPC3, and TRPC4 have promoted insulin secretion by β cells. In rat β cells, TRPC1 and Orai1 are coupled to form cationic channels that mediate Ca²⁺ influx and are regulated by stromal interaction molecule 1(STIM1) (Islam, 2011; Najder et al., 2018; Islam, 2020). STIM1 gates TRPC1 through intermolecular interactions (Islam, 2011; Islam, 2020). In addition, TRPC1 is phosphorylated by protein kinase C-α (PKCα) to promote glucose-induced insulin secretion (Xu et al., 2019). Under normal circumstances, TRPC3 is activated by G protein-coupled receptor 40 (GPR40) in rat and mouse β cells. In rat β cells, Activated TRPC3 enhanced insulin secretion via phospholipase C, PKC, and GPR40, leading to membrane depolarization and Ca²⁺ influx (Hayes et al., 2013). The high expression level of TRPC3/TRPC6 induces pancreatic α and β cells proliferation via insulin-related transcription factor pancreatic and duodenal homeobox 1 (PDX-1) (Hayes et al., 2013). TRPC4 was expressed in rat and mouse islet β cells and insulinoma cells. In βTC3 cells, intracellular Ca²⁺ depletion activates TRPC4, which generates a cationic current that stimulates membrane oscillation and promotes Ca²⁺ influx, thereby increasing insulin secretion (Roe et al., 1998; Islam, 2020). Leptin, the activator of TRPC4, phosphorylates TRPC4 by phosphoinositide 3-kinase. Similarly, in INS-1 cells, protein histidine phosphatase 1 phosphorylates TRPC4, which also translocates K-ATP channels to the plasma membrane typically and promotes insulin secretion (Park et al., 2013; Srivastava et al., 2018).

In addition, in the case of PDAC, TRPC1, TRPC3, and TRPC6 may also be activated by mechanical stimuli to aggravate the disease. In the PDAC pressure microenvironment, TRPC1 transmits the mechanical signal that mediates the activation and migration of pancreatic stellate cells (PSCs) and induces chemotaxis in neutrophils. Furthermore, it was predicted that it cooperated with TRPM7 and TRPV4 to promote the progress of PDAC (Lindemann et al., 2015; Fels et al., 2016; Najder et al., 2018). In the pathological condition of PDAC, activated TRPC3 and K_Ca3.1 (Ca²⁺-dependent K⁺ 3.1) channels in the PDAC matrix jointly promote the migration and taxis of PSCs, and the over-activation of PSCs to produce excessive extracellular matrix proteins is the leading cause of pancreatic cancer fibrosis. Moreover, in the hypoxic tumor microenvironment of PDAC, TRPC6 is not only richly expressed in PSCs but also can be activated by hypoxia, thus promoting the secretion of migration factors, which may also worsen the disease progression, which is also related to its ability to control Ca²⁺ influx (Nielsen et al., 2017; Storck et al., 2017; Najder et al., 2018).

TRPVs are also predominantly expressed in islet β cells. Among them, TRPV2 and TRPV4 also have similar insulin-secreting effects as mentioned above (Islam, 2011; Uchida and Tominaga, 2011; Sawatani et al., 2019). However, TRPV1 transmitting neural sensation does not directly promote insulin secretion, and the role of TRPV5 and TRPV6 in islet remains to be studied. TRPV1 was expressed in INS-1E cells (Fagelskiold et al., 2012). Although TRPV1 does not directly affect glucose-induced insulin secretion in mouse β cells (Diaz-Garcia et al., 2014), it is expressed in sensory nerve fibers of the mouse pancreas, and its locus is associated with the risk of autoimmune diabetes (Razavi et al., 2006; Najder et al., 2018). During insulin release, TRPV1 is activated to promote the release of calcitonin-gene-related peptide (CGRP) and substance P (SP) by neurons, and the concentration of CGRP and SP are balanced with glucose concentration by regulating insulin concentration (Zhong et al., 2019). In nonobese diabetic mice, neuronal failure to release CGRP and SP due to TRPV1 mutations lead to physiological dysfunction of β cells, resulting in insulin resistance and β cell stress (Razavi et al., 2006; Najder et al., 2018; Zhong et al., 2019). In addition, glucagon-like peptide 1 (GLP-1) can also enhance insulin secretion, but different from the above-mentioned TRP channels, TRPV1 in the ileum is activated by capsaicin, which increases GLP-1 secretion and leads to increased pancreatic insulin secretion (Wang et al., 2012); however, this interpretation should be treated with caution. Although TRPV1 is typically excited by capsaicin, whether TRPV1 promotes insulin secretion has been highly controversial (Zhong et al., 2019). Notably, TRPV1 also expresses and mediates inflammation and pain sensation in afferents of acute pancreatitis, in coordination with TRPA1. It is possible that they regulate [Ca²⁺]_i and increase the release of inflammatory and pain mediators (Schwartz et al., 2011; Schwartz et al., 2013).

Ca²⁺ permeable TRPV2 is expressed in mouse insulinoma MIN6 cells and β cells (Islam, 2011). When unstimulated, TRPV2 is distributed in the cytoplasm, mainly in the endoplasmic reticulum (Uchida and Tominaga, 2011). Under high glucose conditions, insulin binds with its β cell receptor, phosphatidylinositol 3 kinase (PI3K), to stimulate the translocation of TRPV2 from the cytoplasm to membrane, which increases [Ca²⁺]_i, accelerates insulin secretion, and stimulates β cell growth (Hisanaga et al., 2009; Aoyagi et al., 2010; Uchida and Tominaga, 2011). In addition, the osmotic swelling of cells during high glucose also activates TRPV2 to depolarize cells and increase glucose-induced insulin secretion (Sawatani et al., 2019). It was also reported that the antiaging gene Klotho translocated TRPV2 in MIN-6 (Lin and Sun, 2012).

As a permeable Ca²⁺ channel, TRPV4 is expressed in human pancreatic non-β cells and, like TRPV2, is a thermosensitive osmotic and mechanical sensor; it is also activated by the swelling of cells stimulated by glucose (Islam, 2011; Uchida and Tominaga, 2011; Marabita and Islam, 2017). Moreover, in mouse β cells, TRPV4 can be activated by sensing mechanical membrane changes induced by human islet amyloid polypeptide, which affect [Ca²⁺]_i and promote insulin secretion (Casas et al., 2008). In addition, the activation of TRPV4 also promotes insulin secretion in INS-1E cells, and extracellular signal-regulated kinase may be involved in this process (Skrzypski et al., 2013; Billert et al., 2017).

TRPV5/6 are the epithelial Ca²⁺ permeable channels. TRPV5 exists in secretory granules of β cells, but its effect on secretion is unknown. TRPV6 is expressed in the exocrine acinar of the pancreas, especially in human and mouse islet α cells (Hoenderop et al., 2003; Marabita and Islam, 2017). In INS-1 cells, TRPV6 regulates calcium ions to influence insulin mRNA expression and cell proliferation, but does not seem to affect insulin secretion (Skrzypski et al., 2015). Pathologically, TRPV6 overexpression in the cytoplasm of pancreatic cancer cells promotes the migration of cancer tissues (Song et al., 2018).

TRPMs are also expressed in the pancreas. In addition to being activated by their activators, TRPM2, TRPM4, and TRPM5 can also be triggered by the influx of Ca²⁺ to participate in membrane depolarization, and TRPM2, TRPM7, and TRPM8 are involved in the progression of pancreatic adenocarcinoma (Islam, 2011; Uchida and Tominaga, 2011; Yee et al., 2012a; Uchida et al., 2017; Islam, 2020). TRPM2 is also engaged in β cell apoptosis in animals other than humans. TRPM2 was found to express in mouse and human β cells and rat INS-1 cells. TRPM2 was activated by ADP ribose (ADPR), Nicotinamide adenine dinucleotide (NAD⁺) concentration, and reactive oxygen species (ROS) to mediate Ca²⁺ influx and depolarization to regulate glucose-dependent insulin secretion (Pi et al., 2007; Du et al., 2009; Leloup et al., 2009; Islam, 2011; Islam, 2020). Particularly, TRPM2 is a calcium-permeable thermosensitive channel. Before being activated by ADPR, extracellular Ca²⁺ must be combined with the calcium sensor in the TRPM2 channel, which reflects the leading role of Ca²⁺ (McHugh et al., 2003; Csanady and Torocsik, 2009; Du et al., 2009). At a high glucose concentration, besides essential ADPR and Ca²⁺, other activators of TRPM2 include arachidonic acid produced by glucose metabolism, PKA-dependent cyclic adenosine monophosphate (cAMP), intestinal incretin hormone GLP-1, and physical second messenger “heat” (Togashi et al., 2006; Islam, 2011; Yosida et al., 2014). Growth hormone-releasing peptides Ghrelin and epinephrine inhibit TRPM2 by inhibiting cAMP, thus inhibiting insulin secretion (Yosida et al., 2014; Islam, 2020).

Moreover, TRPM2 was associated with β cell apoptosis. In the case of oxidative stress induced by free fatty acids or cytokines, TRPM2 is activated by ROS, which promotes mitochondrial destruction and leads to apoptosis. Still, human β cells resist such apoptosis (Wehage et al., 2002; Scharenberg, 2009; Li et al., 2017a; Islam, 2020). In addition, TRPM2 is distributed on the lysosomal membrane, gating Ca²⁺ and Zn²⁺ and affecting the externalization of phosphatidylserine (Mirnikjoo et al., 2009; Li et al., 2017a). In the case of pathological PADC, TRPM2 of neutrophils in tumor stroma may also be activated by ROS (Uchida and Tominaga, 2011; Faouzi and Penner, 2014).

TRPM3 has the permeability of Na⁺, Zn²⁺, and Ca²⁺, and has a strong absorption effect on Zn²⁺. In pancreatic β cells such as INS-1 cells, TRPM3, which is activated by pregnenolone sulfate (PregS), mediates Ca²⁺, Zn²⁺ influx, and induces the biosynthesis of zinc finger transcription factor Egr-1, thereby promoting glucose-induced insulin synthesis and release (Wagner et al., 2008; Colsoul et al., 2011; Mendez-Resendiz et al., 2020). Although the effect of TRPM3 is rapid and reversible, it does not participate in Ca²⁺ signaling in β cells, probably because PregS depolarizes with Na⁺ current and thus activates voltage-gated calcium channels (Islam, 2020). In addition to PregS, TRPM3 is also regulated by phosphatidylinositol 4,5-biphosphate (PIP₂) and heat (Badheka et al., 2015).

Both TRPM4 and TRPM5 are intracellular Ca²⁺ dependent, and they are activated by increased [Ca²⁺]_i during insulin release (Colsoul et al., 2010; Uchida and Tominaga, 2011). Unlike TRPM2, TRPM4/5 are not Ca²⁺ permeable, but monovalent cation channels. Activated by Ca²⁺ influx, TRPM4/5 depolarize the membrane through Na + action and open voltage-gated calcium channels, thereby increasing glucose-induced insulin secretion (Islam, 2011; Uchida and Tominaga, 2011). In addition to being activated by [Ca²⁺]_i, TRPM4/5 can also be activated by PKC, leading to membrane depolarization and increasing insulin secretion (Uchida and Tominaga, 2011; Shigeto et al., 2015; Uchida et al., 2017). TRPM4 and TRPM5 are also different. TRPM4 is expressed in both human and mouse β cells and INS-1 cells, and its depolarization mechanism is almost similar (Uchida et al., 2017). In addition to the PKC pathway, PIP2 also maintains TRPM4 sensitivity to [Ca²⁺]_i concentration, and TRPM4 is inhibited by glibenclamide (Colsoul et al., 2011). Particularly, in pancreatic acinar cells (PACs), the depolarization of TRPM4 inhibits Ca²⁺ influx (Diszhazi et al., 2021). TRPM4 is also involved in glucagon secretion in DTC1-6 of islet α cell line (Colsoul et al., 2011). TRPM5 was highly expressed in rat β cells and insulinoma cells but low in human β cells (Islam, 2020). Stevioside can regulate TRPM5, which may be related to its hypoglycemic effect (Steinritz et al., 2018). Interestingly, TRPM5 acts as a taste receptor and activation of sweet-taste receptors in mouse β cells is mediated by TRPM5, and TRPM5 knockout mice have less sweet taste preference and higher glucose tolerance (Larsson et al., 2015; Islam, 2020).

TRPM6 is not expressed in human β cells, while TRPM7, with the permeability of Mg²⁺, Ca²⁺, and Zn²⁺, is exceptionally abundant in human and mouse β cells, and can regulate [Mg²⁺]_i to promote insulin secretion (Islam, 2020). Importantly, in the case of human pathological pancreatic adenocarcinoma, TRPM7 and TRPM8 are overexpressed and are necessary biomarkers for cancer cell proliferation (Yee et al., 2011; Yee et al., 2012a). In pancreatic adenocarcinoma, sweetbread (SWD) mutations overexpress the suppressor of cytokine signaling 3a (socs3a) gene, resulting in cell cycle arrest in G0-G1 phases, inhibiting pancreatic epithelial cell growth, causing hypoplastic acini and dysmorphic ducts. In this process, TRPM7 of some cells is activated by SWD mutations, which mediates Mg²⁺ influx to inhibit socs3a, thus protecting cells from growth defects and enabling normal aging (Yee et al., 2011; Yee et al., 2012b). On the contrary, TRPM8 can prevent gene-induced senescence of cancer cells, which means that it is beneficial to the proliferation and anti-senescence of pancreatic adenocarcinoma cells and promotes the progression of the disease (Yee et al., 2010).

TRPA1 is a calcium-permeable non-selective cation channel, dual thermoreceptor, which is highly expressed in rat pancreatic cells. It is activated by glycolytic products at high glucose concentrations and positively regulated by estrogens and their metabolites (Uchida et al., 2017; Mendez-Resendiz et al., 2020). In mouse islet β cells and rat INS-1 cells, TRPA1 is directly activated by hydroxylated catechol estrogens such as 2-hydroxyestradiol, which accelerates membrane depolarization and calcium influx through synergistic K-ATP channel closure, thereby increasing glucose-induced insulin secretion (Colsoul et al., 2011; Ma et al., 2019; Mendez-Resendiz et al., 2020). However, long-term stimulation of TRPA1 interferes with the transcription of insulin-related factors such as pancreatic and duodenal homeobox 1 (PDX-1) and reduces insulin secretion (Steinritz et al., 2018).

TRPML1, TRPML3, and TRPP1 are expressed in human pancreatic β cells and islets (Marabita and Islam, 2017). TRPML1 is also a Ca²⁺ osmotic channel, mainly located in intracellular vesicles. Since the activity of TRPML is related to pH, it tends to exist in lysosomes with low pH and can be activated by phosphatidylinositol 3,5-bisphosphate, which is rich in lysosomes. It plays a role in vesicle transport and lysosomal exocrine secretion (Li et al., 2017b; Di Paola et al., 2018). Moreover, TRPML1 mutation can lead to the loss of lysosome function (Sun et al., 2000; Dong et al., 2009). Finally, TRPP1 acts as a Ca²⁺ permeable non-selective cation channel, which may also promote β cell depolarization (Islam, 2020). The detailed molecular mechanism of TRP channels in the pancreas is shown in Figures 2, 3.

Salivary gland secretion depends on the increase of Ca²⁺ in salivary gland cells; when both extracellular and endoplasmic reticulum (ER) Ca²⁺ are insufficient to maintain the concentration gradient, the Store-Operated Ca²⁺ Entry (SOCE) mechanism mediates [Ca²⁺]_i (Ambudkar, 2016; Liu et al., 2018). Thus, ion transporters and channels such as Na⁺/K⁺/2Cl⁻ cotransporter 1 (NKCC1), Anoctamin 1 (ANO1), and K_Ca are opened to regulate intracellular and extracellular Cl⁻ concentration and maintain osmotic gradient, allowing water to be secreted through the water channel Aquaporin 5 (AQP5) in the apical membrane (Ambudkar, 2012; Ambudkar, 2014; Liu et al., 2018). In this process, the channels involved in SOCE are mainly TRPC1 and Orai1. Orai1 is an important component of store-operated calcium release-activated calcium and SOC channels, and the role of TRPC1 depends on the activity of the Orai1 channel (Liu et al., 2000; Liu et al., 2007; Cheng et al., 2008; Cheng et al., 2011; Hong et al., 2011; Ambudkar, 2016). Orai1 is first activated to mediate Ca²⁺ influx, which stimulates the movement of TRPC1 to the plasma membrane after the acinar cells are stimulated by neurotransmitters. Moreover the two channels are coupled into a single channel to increase Ca²⁺ influx and salivary secretion by activating an ER- Ca²⁺ binding protein- STIM1 and Caveolin-1 (Zeng et al., 2008; Pani et al., 2009; Cheng et al., 2011; Hong et al., 2011; Pani et al., 2013; Choi et al., 2014; Ambudkar, 2016; Liu et al., 2018).

Except for TRPC1, TRPC3 and TRPC4 also participate in SOCE, but whether TRPC3 participates in SOCE seems to be related to cell type and expression level (Liu et al., 2018). In salivary gland ductal cells, TRPC3 acts in a similar way to TRPC1 that TRPC3 is also associated with Orai1 after being activated by STIM1. However, TRPC3 must bind to TRPC1 before activation; that is, TRPC3 is dependent on TRPC1 to form TRPC3-TRPC1 heteromeric channel (Lee et al., 2014; Ong et al., 2014; Ambudkar, 2016). In pathological conditions, the generation of cytotoxicity in salivary acinar cells during inflammation is related to the Ca²⁺ influx mediated by TRPC3, which is reflected in ROS production and membrane damage. This phenomenon is similar with the increased of [Ca²⁺]_i in pancreatic acinar cells aggravating pancreatitis. It is suspected that TRPC1 is also involved in this cell damage process (Kim et al., 2011; Ambudkar, 2016).

Loss of salivary gland function leads to xerostomia, often caused by radiation therapy or chronic autoimmune disease Sjögren’s syndrome (pSS), which is associated with an unregulated increase in intracellular Ca²⁺ (Konings et al., 2005; Mavragani and Moutsopoulos, 2014; Liu et al., 2018). For the loss of salivary gland function caused by pSS, pSS itself leads to the overexpression of TNF-α, interleukin, γ-IFN, and other inflammatory factors (Baturone et al., 2009; Bikker et al., 2010). Moreover, activated granulocytes also increase ROS during inflammation, which is regulated by TRPM2. TRPM2 regulates immune inflammation by regulating the release of inflammatory factors and the growth of dendritic cells (Gasser et al., 2006; Yamamoto et al., 2008; Sumoza-Toledo et al., 2011; Knowles et al., 2013).

TRPM2 is the ROS receptor existing in mouse salivary acinar cells, which may be involved in radiation-induced cell damage and pSS (Sumoza-Toledo and Penner, 2011; Liu et al., 2013; Liu et al., 2018). TRPM2 is activated by NAD+ and its ADPR generated after hydrolysis to guide Ca²⁺ influx and participate in cell damage when the radiation creates an excessive ROS microenvironment (Perraud et al., 2003; Sumoza-Toledo and Penner, 2011; Ambudkar, 2016; Liu et al., 2018). TRPM2 plays a key role in the relationship between cell damage after radiation and dry mouth (Liu et al., 2013; Teos et al., 2016; Liu et al., 2018). In conclusion, TRPM2 mediates irreversible salivary gland damage after radiation by excessive consumption of STIM1 and dysregulation of SOCE (Liu et al., 2013; Liu et al., 2017). For the recovery of damaged glands after radiation, inhibition of TRPM2 activation can promote the regeneration of glandular cells by keeping STIM1 and SOCE at normal levels (Jang et al., 2016; Liu et al., 2017). Moreover, TRPM2 was not only associated with salivary gland secretion loss, but also inhibited the abnormal shrinkage of acinar cell volume, which is related to the change of osmotic pressure during salivary gland secretion (Ambudkar, 2016). For example, TRPM2 is activated after radiation to regulate ion transporters, changes osmotic gradients, and normalizes cell size through regulatory volume increase (RVI) under the condition of being excited by agonists such as carbachol (CCh) (Liu et al., 2018). In contrast to TRPM2’s RVI, swollen cells that absorb water can return to normal size by the opposite route, known as regulatory volume decrease (RVD). TRPV4 can be activated under hypotonic conditions and play an RVD role by regulating osmotic gradient by guiding Ca²⁺ influx as well (Liu et al., 2006; Liu et al., 2018). Additionally, TRPV4 also can be activated by 4α-phorbol-12,13 didecanoate, Muscarine, GSK1016790A, and heat. Muscarine leads to salivary secretion by activating TRPV4 through heat, which opens the Cl⁻ transport channel ANO1 (Zhang et al., 2012a; Sobhan et al., 2013; Derouiche et al., 2018).

Among them, TRPV1, TRPM8, TRPV3 and TRPV6 are also found in salivary glands. TRPV1 agonists-capsaicin, piperine, or TRPM8 agonist -menthol increased CCh-induced salivary secretion. Allyl isothiocyanate, the co-antagonist of TRPM8 and TRPA1, decreased the salivary secretion, indicating that the roles of these TRP channels are different (Peng, 2011; Sobhan et al., 2013; Liu et al., 2018; Houghton et al., 2020). TRPC1, TRPV4, TRPM8, and TRPV3 are also involved in the early tubular structure differentiation of salivary gland cells (Fujiseki et al., 2017). The detailed molecular mechanism of TRP channels in the salivary gland is shown in Figure 4.

The adrenal gland is a vital endocrine organ of the human body. The gland is divided into two parts, the adrenal cortex and the adrenal medulla (AM). The chromaffin cells in the medulla secrete catecholamine hormones, and the cortex mainly secretes corticosteroids, including aldosterone and glucocorticoids. These hormones always affect the function of the human body, and their balance is of great significance to human health. Many subfamilies of TRP channels are expressed in the adrenal gland and play a significant role in adrenal physiology and pathology.

It has been confirmed that TRPC1, TRPC4, and TRPC5 are expressed in guinea pig AM cells at the protein level. Keita et al. found that STIM1 promotes the formation of TRPC1 with TRPC4 heteromer channels as well as insertion into the cell membrane in PC12 cells and guinea pig AM cells (Harada et al., 2019). TRPC1—TRPC4 heteromeric channels function as store-operated Ca²⁺ entry channels in endothelial cells (Sundivakkam et al., 2012). And TRPC3 (Goel et al., 2007), TRPC5 (Bezzerides et al., 2004), and TRPC6 (Cayouette et al., 2004) are inserted into the cell membrane in response to stimulation by G protein-coupled receptors (GPCRs) or receptor tyrosine kinases. TRPC1—TRPC4 heteromeric channels, therefore, mediate Ca²⁺ influx in response to stimulation of muscarinic receptors in guinea pig AM cells.

TRPC channels expression in the adrenal gland is increased in patients with metabolic syndrome, which may be a potential risk of inducing cardiovascular disease (Hu et al., 2009). Renin-angiotensin-aldosterone system activity is significantly increased in metabolic syndrome (Krug and Ehrhart-Bornstein, 19792008; Sarzani et al., 2008). High concentrations of aldosterone can regulate gene expression through corresponding receptors, which include binding to the glucocorticoid response element (GRE) half-site sequence (Olivos and Artalejo, 2008; Bhargava et al., 2004). Mineralocorticoid and glucocorticoid receptors bind to the same response element in the promoter, the GRE. Several GRE-like half-site motifs (AGAACA) were present in the putative promoter region of TRPC1, TRPC5, and TRPC6 channels. These channels are up-regulated in patients with metabolic syndrome. When these channels are activated via the G_q/11-PLCβ pathway or Ca²⁺ store depleting pathway (Marom et al., 2011), an influx of Ca²⁺ into chromaffin cells causes depolarization of chromaffin cells and may activate voltage-gated Ca²⁺ channels to promote their secretion of epinephrine (Burgoyne et al., 1993; Cheek and Barry, 1993). The detailed molecular mechanism is shown in Figure 5. In addition, circulating hormones, such as histamine and angiotensin II, can also stimulate catecholamine exocytosis from adrenal chromaffin cells by activating voltage-independent circulating hormone-operated cation channels (Livett and Marley, 1993; Olivos and Artalejo, 2008; Sala et al., 2008). TRPC1, TRPC5, and TRPC6 are candidates for increasing hormone-induced exocrine secretion in chromaffin cells (Obukhov and Nowycky, 2002). It is well-known that excessive release of epinephrine from the adrenal gland increases the risk of myocardial infarction, cerebrovascular accident, arrhythmia, stroke, while up-regulated TRPC1, TRPC5, and TRPC6 channels are likely to cause cardiovascular disease in patients with metabolic syndrome. Therefore, these channels in the adrenal gland may be a therapeutic intervention target in patients with metabolic syndrome. However, it is not clear whether aldosterone is the only regulator of TRPC channels in the adrenal medulla, and additional molecular factors that further up-regulate TRPC channels may exist during metabolic syndrome.

TRPV1 is a polymodal receptor activated by physical and chemical stimulation, including heat (above 43°C) and changes in pH (both acidic and alkaline), endovanilloids, such as anandamine, N-acyldopamines, and a variety of exogenous agonists, which mainly consist of capsaicin (Zsombok, 2013; Moran and Szallasi, 2018). TRPV1 was upregulated in chromaffin cells of neuropathic animals (Arribas-Blázquez et al., 2019). Meanwhile, Pablo et al. found that stress significantly increased the mRNA levels of TRPV1 channels in adrenal cells (Surkin et al., 2018). TRPV1 is a ligand-gated, non-selective cation channel with high permeability to Ca²⁺ and therefore Ca²⁺ influx in adrenocortical cells when TRPV1 is activated (Moran and Szallasi, 2018). High levels of intracellular Ca²⁺ concentration may suppress glucocorticoid production (Matthews and Saffran, 1973). Capsaicin inhibits lipopolysaccharide-induced intracellular steroidogenesis in adrenocortical cells by activating TRPV1 and increasing intracellular Ca²⁺ levels, which may prevent the development of central nervous system disorders in patients with severe sepsis (Ferreira et al., 2019). In summary, TRPV1 channels in the adrenal gland are upregulated when the body is under stress or neuropathological conditions. Excessive expression of TRPV1 after activation by its agonists may attenuate the release of corticosteroids to some extent and thus protect the body. Finally, TRPV1 is a driver to increase the rapid release of corticosterone and epinephrine. Dekel et al. proposed an alternative strategy to modulate peripheral organ function (Rosenfeld et al., 2020). They developed a magnetothermal switch for the on-demand release of the adrenal hormones epinephrine and corticosterone by controlling TRPV1 activation in vitro. They use this approach to control adrenal hormone secretion in genetically intact rats wirelessly. Since alterations in the levels of these hormones are associated with psychiatric disorders such as post-traumatic stress disorder and depression, their approach may be helpful to study the physical and psychological effects of stress. While TRPV1 (and other thermosensitive TRP channels) was shown to be expressed in other organs deep in the body, such as peripheral nerves, gastrointestinal tract, pancreas, and heart (Akbar et al., 2008; Schwartz et al., 2011; Randhawa and Jaggi, 2017), the potential application of magnetothermal deep organ stimulation as means to study organ function paves the way for the development of bioelectronic medicines.

TRPA1 is a Ca²⁺ -permeable non-selective cation channel that can be activated by various toxic or irritating substances in nature. Allyl isothiocyanate (AITC) and cinnamaldehyde (CAN) increase epinephrine secretion by activating TRPA1-expressing adrenal sympathetic nerves in rats (Iwasaki et al., 2008). TRPA1 is frequently coexpressed with TRPV1, raising the possibility that TRPA1 and TRPV1 mediate the function of a class of polymodal nociceptors (Liedtke and Heller, 2007). Yuriko et al. found that oleuropein aglycone (OA) stimulates norepinephrine secretion by activating TRPA1 and TRPV1, thereby enhancing UCP1 receptor expression in brown adipose tissue (BAT) (Oi-Kano et al., 2017). BAT is the organ responsible for heat production in the human body, and activation of adrenergic receptors expressed in BAT can increase UCP1 receptor expression (Himms-Hagen et al., 1994; Nagase et al., 1996; Cannon and Nedergaard, 2004). The activation of TRPV1 is a key link in capsaicin-induced epinephrine secretion. Capsaicin improves body energy metabolism by promoting catecholamine secretion and up-regulating UCP1 receptor in rats (Kawada et al., 1986; Watanabe et al., 1987; Watanabe et al., 1988; Kobayashi et al., 1998). Also, AITC increases body heat production and expression of UCP1 receptors by activating TRPA1 channels (Yoshida et al., 1988). We hypothesize that TRPA1, when expressed alone, can be activated by its agonist AITC, thereby inducing catecholamine secretion from the adrenal gland. Activation of TRPA1 is therefore likely to be one of the pathways by which the body increases energy metabolism as well as increases heat production, but there is currently insufficient evidence to elucidate the mechanism by which TRPA1 mediates catecholamine secretion after activation. However, not all TRPA1 activation can mediate the increased activity of adrenal sympathetic nerves. Some studies have found that β-eudesmol inhibits adrenal sympathetic nerve activity (ASNA) by activating TRPA1 (Ohara et al., 2018). Kazuaki et al. identified three key amino acid residues in TRPA1, namely threonine 813, tyrosine 840, and serine 873, which can be activated by β-eudesmol (Ohara et al., 2015).

TRPM7 has a very broad tissue distribution as a member of the TRP channel superfamily. Its gene encodes a persistently open calcium channel regulated by intracellular Mg²⁺/ATP. It has been shown that calcium influx caused by TRPM7 plays a key role in the survival of cells (Nadler et al., 2001). Bonnie et al. found that rat adrenal pheochromocytoma (PC12) cells expressing the receptor (LEPRb) showed significant induction of promoter activity and TRPM7 expression after leptin treatment (Yeung et al., 2021). They found that activated pSTAT3 epigenetically regulates the transcription of TRPM7 through DNA methylation and histone modifications. Specifically, it is manifested in a reduction in CpG site-specific methylation and H3K27 (H3 [histone 3] K27 [lysine 27]) trimethylation and an increase in H3K27 acetylation and H3K4 (H3 lysine 4) trimethylation at the TRPM7 promoter. The detailed molecular mechanism is shown in Figure 6. Therefore, TRPM7 channels may be up-regulated when plasma levels are increased in vivo due to obesity, and we speculated that when this event occurs in adrenal chromaffin cells, more Ca²⁺ influx due to up-regulation of TRPM7 channels may induce increased catecholamine secretion, which is likely to be one of the reasons associated with hypertension. Fortunately, epigenetic changes are reversible, and epigenetic modifications targeting TRPM7 may serve as a novel therapeutic approach for the treatment of obese hypertension.

TRPM4 has been demonstrated to be expressed in mouse adrenal medulla (AM) cells at the mRNA levels (Mathar et al., 2010a). Masumi et al. found that pituitary adenylate cyclase-activating polypeptide (PACAP) induced catecholamine secretion in mouse AM cells, which may be due to the generation of depolarizing inward currents caused by TRPM4 channel activation (Inoue et al., 2020). Application of the endogenous PKC activator 1-oleoyl-2-actyl-sn-glycerol mimics PACAP activation of Na⁺ -permeable cation channels in bovine AM cells (Tanaka et al., 1996), and therefore, PACAP may also activate TRPM4 in an AM-cell PKA-dependent manner. Differently, PACAP does not directly induce the secretion of catecholamines in guinea-pig AM cells, but rather promotes muscarinic receptor-mediated activation of Ca²⁺-activated nonselective cation (NSC) channels, and this promotion is mainly due to the increased insertion of heteromeric TRPC1-TRPC4 channels into the cell membrane (Harada et al., 2019). Ilka et al. found that mice with Trpm4 gene deletion lost long-term regulation of blood pressure stability, which they concluded was caused by elevated plasma levels of epinephrine and norepinephrine after excluding the cause of altered cardiac function (Mathar et al., 2010b). However, the molecular mechanism of how TRPM4 regulates or promotes release from chromaffin cells remains to be clarified but may include direct dependence on TRPM4 to regulate vesicle release, as shown for another TRPM7 in cholinergic synaptic vesicles (Krapivinsky et al., 2006). These results suggest that TRPM4 activity may be beneficial in limiting elevated blood pressure in hypertensive patients. Hypertension is a potential risk factor for cardiovascular disease. In most cases, its pathogenesis remains unclear. The above lists two TRPM channels that affect the body’s blood pressure level by changing the secretion of catecholamines by adrenal chromaffin cells, demonstrating the feasibility of TRP channels as a therapeutic target for hypertension, but there are still not many studies in this area and the mechanism by which TRP channels regulate blood pressure needs to be further explored.

The widely distributed TRPV4 cationic channel participates in the transduction of mechanical and/or osmotic stimuli in different tissues (Liedtke and Friedman, 2003; Gao et al., 2003). TRPV4 is selectively localized in the basolateral membrane compartment, where it is activated by 4-a-phorbol12,13-didecanoat (4a-PDD) (Vriens et al., 2007), resulting in calcium entry, which on the one hand activates Ca²⁺-activated K⁺ channels (BK) and provides a transcellular ion pathway. On the other hand, it increases the permeability of mammary epithelial cells, which is created by a down-regulation of sealing-type claudin proteins accompanied by an altered tight junction structure (Reiter et al., 2006). The detailed molecular mechanism is shown in Figure 7. Md Aminul et al. found that both low permeability tight junctions of mammary epithelial cells and milk production were enhanced after a mild heat treatment at 39°C. TRPV4 activity was increased during mild heat treatment at 39°C. Activation of TRPV4 by GSK1016790A leads to Ca²⁺ influx, promotes Ca²⁺ release from the endoplasmic reticulum (ER), and depletes Ca²⁺ stores, at which point the unfolded protein response (UPR) is initiated and upregulates the transcript levels of Xbp1s through PERK, IRE1, and ATF6 receptor-mediated signaling pathways (Harding et al., 2000; Celli et al., 2011; Shen et al., 2019). Upregulation of the Xbp1 gene increases the expression of β-casein (β-casein is a differentiation marker of HC11 cells and is a representative milk protein), Zo-1, ocln, and Cldn3 mRNA, and thereby regulates the expression of TJ protein-coding genes. Interestingly, TRPV4 expression is increased during pregnancy but decreased during lactation (Islam et al., 2020). Mammary epithelial cells are exposed to temperatures above body temperature during lactation due to metabolism (Berman et al., 1985). Heat stress induces ER stress and causes UPR (Xu et al., 2011; Kim et al., 2013). Elevated transcript levels of Chop decrease the viability of cells and therefore cause reduced lactation (Urra et al., 2013). The detailed molecular mechanism is shown in Figure 8. TRP channels cover the temperature sensing range, TRPV4 is activated at 39°C, but there may be other TRPs that are activated at higher temperatures, and although there is no evidence so far, it provides direction and ideas for later studies.

TRPV6 is expressed in normal breast and breast cancer cell lines. A positive correlation between expression of the transcription factor zinc finger homeobox 3 (ZFHX3) and promoter activity of TRPV6 was found by Dan et al. (Zhao et al., 2019). Previous studies have shown that Ca²⁺ influx mediated by TRPV6 activation is able to induce keratinocyte differentiation (Lehen’kyi et al., 2011; Lehen’kyi et al., 2007). Ca²⁺ has been shown to be involved in controlling the growth of breast cancer cells through its interaction with calmodulin (Strobl et al., 1995). TRPV6 channel-mediated Ca²⁺ influx is involved in cell proliferation, which may be associated with breast cancer cell migration (Bolanz et al., 2008; Bolanz et al., 2009).

TRPC1 expression is increased in invasive ductal carcinoma (Guilbert et al., 2008; Dhennin-Duthille et al., 2011; Mandavilli et al., 2012). TGFβ-induced Epithelial-to-Mesenchymal Transition (EMT) is dependent on Ca²⁺ entry via the TRPC1- Stromal Interaction Molecule 1 (STIM1) complex that leads to the activation of calpains and matrix metalloproteinases (MMPs), which target proteins involved in cellular adherence and promote their migration (Schaar et al., 2016). The detailed molecular mechanism is shown in Figure 9. Therefore, inhibition of the TRPC1-STIM1 complex may be an attractive target for the treatment of breast cancer metastasis. Naoya et al. found that LPA/LPAR3 signaling and subsequent TRPC3 activation leaded to an increase in the number of breast cancer stem cells (BCSCs) through calcium-dependent transcriptional activation of IL-8 by NFAT (Hirata et al., 2022). Polyunsaturated fatty acids (PUFA) and TRPC3 antagonists continuously inhibit the proliferation and migration of breast cancer cells (Zhang et al., 2012b), but the mechanism is still unclear. As one of the biomarkers of breast cancer development and migration, TRPC3 represents a potential target for a new class of anticancer drugs. In the future, specific therapeutic approaches to reduce tumorigenesis may be established by targeting the LPA/LPAR3 pathway and TRPC3 channels. Overexpression of TRPC5 induces chemoresistance by up-regulating of P-glycoprotein (P-gp) and hypoxia-inducible factor-1α in chemoresistant breast cancer cells (Zhu et al., 2015; Ma et al., 2012a). TRPC5-mediated Ca²⁺ entry stimulates P-gp overproduction through NFATc3 in breast cancer cells (Ma et al., 2012b). P-gp expels intracellular Adriamycin (ADM) into the extracellular matrix, leading to drug resistance. The detailed molecular mechanism of TRPC3 and TRPC5 is shown in Figure 10. In addition, TRPC5 mediates cytoprotective autophagy through the CaMKKβ/AMPKα/mTOR pathway, causing drug resistance in breast cancer cells (Zhang et al., 2017). Inhibition of P-gp activity and avoidance of autophagy is therefore an attractive approach to overcome multidrug resistance in cancer chemotherapy, and TRPC5 is a valuable target.