Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin

Abstract

BACKGROUND Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature. METHODS Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors. RESULTS Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways. CONCLUSIONS TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.

Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

“…Wnt proteins are cysteine-rich glycosylated proteins that oversee processes such as neuronal development, immunity, angiogenesis, fibrosis, stem cell proliferation, and tumorigenesis (12-14). Wnt and β-catenin signaling can block autophagy (15), apoptosis (16), affect sensory modalities (17), and lead to stem cell proliferation (18-20). However, these pathways can promote angiogenesis (21-23) and lead to tumor growth (24-29) that may align with the proliferative pathways of clock genes such as TIMELESS.…”

“…mTORC1 contains the components Raptor, Deptor (DEP domain-containing mTOR interacting protein), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8/GβL) (27). mTORC2 contains Rictor, Deptor, mLST8, the mammalian stress-activated protein kinase interacting protein (mSIN1), and the protein observed with Rictor-1 (Protor-1) (17, 42). …”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…In contrast, once the destruction of cellular DNA occurs, it is usually not considered to be completely reversible (59). Apoptosis in the nervous system can be involved in retinal degeneration (24, 76), pain sensitivity and neuronal injury (77), Aβ injury (13, 78–82), epilepsy (83, 84), Parkinson’s disease (11, 41, 85–87), diabetic injury (14, 17, 26, 88–90), traumatic brain injury (41, 91–93), and autism (94). …”

“…mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1. mTOR controls multiple functions that determine the transcription of genes, proliferation and senescence of cells, protein formation, cellular metabolism, and cellular longevity (9, 57, 77, 129, 130). Melatonin, a pineal hormone that controls circadian rhythm, relies upon autophagy pathways and mTOR to control processes of aging and neurodegeneration (131).…”

Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus

“…Autophagy acts as a central regulator of AGTR1/TRPV1-mediated effects [18,35]. It is initiated by stress through different mechanisms, which causes autophagosomes to fuse with lysosomes to form autolysosomes, resulting in degradation of the cargo.…”