Structure–Function Relationship and Physiological Roles of Transient Receptor Potential Canonical (TRPC) 4 and 5 Channels

Abstract

The study of the structure–function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure–function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure–relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms.

Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury

“…The observed asymmetrical changes in TRPC4 and TRPC5 after TBI requires further investigation and focus on cell-type specificity. The heteromerization of TRPC channels remains a complex and unresolved area of investigation ( Kim et al, 2019 ). TRPC5 has an established role in the development and neurite outgrowth with some localization to presynaptic terminals ( Greka et al, 2003 ), which may indicate a greater role of TRPC5 in the maintenance of homeostasis.…”

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Although breast cancer bone metastases are predominantly osteolytic, 15-20% of cases have a predominant osteoblastic component [21][22][23][24]. In normal conditions, several bone modifications occur within the physiological process of bone remodeling [6,25]. When the rate of bone resorption exceeds osteogenesis, bone density decreases but remains close to normal levels [26,27].…”

“…In contrast, osteoblasts secrete osteoprotegerin (OPG), a soluble decoy receptor for RANKL, which inhibits RANK/RANKL signaling negatively regulating osteoclastogenesis [52][53][54]. Of note, osteoclast differentiation may also be elicited by IL6, IL1, prostaglandins, and M-CSF-mediated stimulation of bone marrow macrophages [25,55,56]. Upon activation, osteoclasts reabsorb the bone by producing hydrochloric acid and metalloproteases, which dissolve the mineral in bone and cause the breakdown of the collagenous matrix, respectively [57].…”

Anti-Osteoporotic Effect of Morroniside on Osteoblast and Osteoclast Differentiation In Vitro and Ovariectomized Mice In Vivo

“…Bone remodeling is regulated by the balance between osteoclasts (bone resorption) and osteoblasts (bone formation) [1]. Deficits in osteoclast differentiation are one of the major causes of skeletal diseases, such as osteoporosis [27,28].…”

“…Osteoporosis is a common skeletal disorder characterized by bone mineral density (BMD) loss caused by the dysregulation of bone homeostasis, including bone resorption by osteoclasts and bone formation by osteoblasts [1]. The imbalance between the two orchestrated processes leads to weak and brittle bone, increasing the risk of bone diseases such as osteoporosis [2].…”