TRPC channels in exercise-mimetic therapy

Abstract

Physical exercise yields beneficial effects on all types of muscle cells, which are essential for the maintenance of cardiovascular homeostasis and good blood circulation. Daily moderate exercise increases systemic antioxidative capacity, which can lead to the prevention of the onset and progression of oxidative stress-related diseases. Therefore, exercise is now widely accepted as one of the best therapeutic strategies for the treatment of ischemic (hypoxic) diseases. Canonical transient receptor potential (TRPC) proteins are non-selective cation channels activated by mechanical stress and/or stimulation of phospholipase C-coupled surface receptors. TRPC channels, especially diacylglycerol-activated TRPC channels (TRPC3 and TRPC6; TRPC3/6), play a key role in the development of cardiovascular remodeling. We have recently found that physical interaction between TRPC3 and NADPH oxidase (Nox) 2 under hypoxic stress promotes Nox2-dependent reactive oxygen species (ROS) production and mediates rodent cardiac plasticity, and inhibition of the TRPC3-Nox2 protein complex results in enhancement of myocardial compliance and flexibility similar to that observed in exercise-treated hearts. In this review, we describe current understanding of the roles of TRPC channels in striated muscle (patho)physiology and propose that targeting TRPC-based protein complexes could be a new strategy to imitate exercise therapy.

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

“…Numerous studies have provided very rich information concerning the physiological significance and pathophysiological roles of individual TRPC isoforms. Many of these studies have been included in recent comprehensive review articles and book chapters that focus on specific organ/tissue system or disease, including cardiovascular system (Yue et al, 2015;Alonso-Carbajo et al, 2017;Xiao, Liu, Shen, Cao, & Li, 2017;Avila-Medina et al, 2018), with emphasis on vascular endothelial and smooth muscle cells (Beech, 2013;Earley & Brayden, 2015;Ampem et al, 2016;Grayson, Murphy, & Sandow, 2017), cardiac remodeling (Falcon et al, 2019), cardiac fibrosis (Numaga-Tomita et al, 2017), atrial fibrillation (Han & Li, 2018) and therapeutic angiogenesis (Moccia, Lucariello, & Guerra, 2018); skeletal muscles (Numaga-Tomita et al, 2019;Sauc & Frieden, 2017); lung and lung diseases (Smith, Ayon, Tang, Makino, & Yuan, 2016;Malczyk et al, 2017;Dietrich, Steinritz, & Gudermann, 2017); kidney and kidney diseases (Schlondorff, 2017;Staruschenko, Spires, & Palygin, 2019;Zhou & Greka, 2016); salivary gland physiology and dysfunction (Ambudkar, 2016), reproduction and sperm function (Götz, Qiao, Beck, & Boehm, 2017;Kumar et al, 2018); immune system and inflammation (Ramirez et al, 2018); and many different aspects of nervous systems and neurological diseases, e. g. neurological functions (Sun et al, 2014); neurotransmission and hormone sensing as well as glucose sensing (Fioramonti, Chrétien, Leloup, & Pénicaud, 2017) in the hypothalamus, neural development (Feng, He, Li, & Wang, 2015;Tai & Jia, 2017), neurological diseases especially neurodegeneration (Pchitskaya, Popugaeva, & Bezprozvanny, 2018;Secondo, Bagetta, & Amantea, 2018;Wang et al, 2017), Alzheimer's disease…”

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Indirect and direct interactions between Ca 2+ transporters and ROS producing enzymes have been reported. For instance, physical interaction between TRPC3 and NOX2 contributes to ROS production under hypoxic stress and mediates cardiac plasticity [ 83 ]. Various Ca 2+ transport proteins of the plasma membrane are affected by ROS.…”

TRP Channels Role in Pain Associated With Neurodegenerative Diseases

“…All TRPC are non-selective cation channels permeable to Ca 2+ (Bon and Beech, 2013) linked to cellular processes such as cell division, differentiation, apoptosis, transduction of external stimuli, and refill of intracellular Ca 2+ stores. In addition, they act amplifying receptor-activated Ca 2+ signaling via interaction with second messengers (Numaga-Tomita et al, 2019). TRPC channels are widely distributed in cells of different tissues, including brain, heart, smooth muscle, liver, testis, ovaries, salivary glands (Beech et al, 2003), endothelium, kidneys (Freichel et al, 2005), and adrenal glands (Philipp et al, 2000).…”