Abstract
Chronic pathological pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Despite much progress we have made in understanding chronic pain in the last decades, its underlying mechanisms remain elusive. It is assumed that abnormal increase of calcium levels in the cells is a key determinant in the transition from acute to chronic pain. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is therefore helpful towards understanding the development of chronic, pathological pain. Canonical transient receptor potential (TRPC) channels form a subfamily of nonselective cation channels, which permit the permeability of Ca2+ and Na+ into the cells. Initiation of Ca2+ entry pathways by these channels triggers the development of many physiological and pathological functions. In this review, we will focus on the functional implication of TRPC channels in nociception with the elucidation of their role in the detection of external stimuli and nociceptive hypersensitivity.
Highlights
Chronic pathological pain represents a major challenge to clinical practice and basic science
Mobilization of intracellular Ca2+ upon neuronal activation is the main trigger for activation of a variety of signaling mediators, such as CamKII-alpha, Protein Kinase A, and extracellular receptor-activated kinases (ERK1/2); these, in turn, regulate the expression and functions of downstream proteins determining the excitability of neurons, which are involved in pain processing [1, 2]
On the basis of amino acid homology, transient receptor potential (TRP) superfamily is divided into six subfamilies, TRP canonical or classical (TRPC), TRP vanilloid (TRPV), TRP melastatin (TRPM), TRP ankyrin (TRPA), TRP polycystin (TRPP), and TRP mucolipin (TRPML) [4,5,6,7,8,9]
Summary
Chronic pathological pain represents a major challenge to clinical practice and basic science. Activity-dependent neural plasticity is assumed to be a prime mechanism underlying various physiological and pathological processes including clinical transitions from acute, physiological pain to chronic, pathological pain [1, 2]. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is helpful towards understanding the development of chronic, pathological pain. With the establishment of specific TRPC subunit transgenic mouse models and discovery of selective pharmacological tools at TRPC subunits during the past few years, emerging evidence has accumulated that TRPC subfamily exert an important role in a variety of neuronal functions, including memory, motor coordination, fear, anxiety, Huntington’s disease, neurite growth, and pain [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Recent advances in the development of therapeutic strategies targeting against TRPC subfamily will be reviewed
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