China
Africa
Explore chapters and articles related to this topic
Recording Ion Channels in Cilia Membranes
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Leo C.T. Ng, Amitabha Mukhopadhyay, Thuy N. Vien, Paul G. DeCaen
Like the on-cilia configuration, channel biophysics are measured at the single-channel level in the enveloped excised cilia patch clamp configuration.50 This patch configuration was first adapted to record primary cilia currents by the Kleene laboratory from methods used to record ionic currents found in frog sensory olfactory cilia.51 Importantly, the difference between the “enveloped cilia” and “on-cilia” configurations is where these seals are made with the glass electrode. Here, the entire cilium is enveloped within the patch electrode, and the physical seal is made at the junction between the cilia and cell membrane. The reporting conventions regarding command and current directionality are the same as the “on-cilia” configuration. The enveloped cilia patch can be torn off from the cell body to expose the inner membrane of the cilia. In this configuration, ion channels which might be electrically insulated from the primary cilia patch configuration—such as those localized to the membrane of the cilia-cell junction—can be measured. An advantage of this configuration is that these populations might be missed in the other cilia membrane patch clamp configurations. The Kleene group has determined that TRPM4 is at least in-part responsible for a 31 pS cation conductance using the enveloped cilia patch configuration.60 In our hands, we do not observe this conductance in the on-cilia patch configuration. However, we regularly see the TRPM4 and polycystin-2 conductance in the enveloped cilia patch configuration from IMCD cells. These findings suggest that these two channel populations may reside at different locations within the membrane of the cilium or at the ciliary-cell junction.
Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
TRP channels are present in both the adaptive and the innate immune cells and act as mediators to conduct Ca2+, Mg2+ (TRPM2, TRPM6, TRPM7), and Na+ (TRPM4). As described earlier, the major role of some of the TRP channels is to modulate intracellular Ca2+ in immune cells and, thus, influence their function. They have been established to play a role in phagocytosis, immune cell migration, and the release of inflammatory cytokines. It is known that, following TCR stimulation, TRPM2 channels become activated probably via release of cyclic ADP ribose (ADPR) from the ER, which is involved in their proliferation and pro-inflammatory cytokine secretion59,60. Moreover, TRPM2 deficiency mitigated the development of encephalomyelitis in mice61. TRPM2-mediated Ca2+ signaling was also shown to be involved in the maturation of DCs through modulation of the processing of MHC class II molecules62. The absence of TRPM4 channels in DCs led to impaired migration due to disruption of Ca2+ homeostasis60. In addition, phagocytic activity and cytokine release by macrophages were diminished in TRPM4-deficient mice60. B cells lacking a TRPM7 channel exhibited an inability to proliferate and an increased death rate60. In the case of T cells as well, mice lacking T cell–specific TRPM7 showed a defect in T cell development60. There are also other members of this channel group that have been studied extensively and shown to be important in modulating immune cell function and development and inflammatory diseases60. Due to their key role in immune cell maturation and activation, they are also considered to be a great therapeutic target against autoimmune disorders, like rheumatoid arthritis, type I diabetes, lupus erythematosus, and multiple sclerosis, and thus need to be evaluated clinically.
Ion Channels of Reward Pathway in Drug Abuse
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Transient receptor potential (TRP) channels are a large family of non-selective cation channels. Besides traditional ligand-gated opening, mechanical force, chemical stress, and temperature also can lead to channel opening. Most TRP channels are permeable to Ca2+ with the exceptions of TRPM4 and TRPM5, which are only permeable to monovalent cations. The TRP superfamily contains six groups: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPV (vanilloid). TRP channels were first identified in Drosophila melanogaster, and studies have found around 30 channels in mammals belonging to this superfamily. The diverse activation mechanisms and expression of these channels make them involved in a wide range of activities of the central and peripheral nervous systems. However, the roles of these channels in drug abuse have only recently begun to be explored, with one of the most thoroughly studied families of TRP channels in drug abuse being the TRPV family. The TRPV family contains six mammalian members: TRPV1-6. TRPV1-4 are all heat-activated channels, which exhibit cation non-selectivity and modest Ca2+ permeability. TRPV5 and TRPV6 are the only highly Ca2+-selective channels in the TRP family, and both are regulated by [Ca2+]i. In contrast with other TRPVs, the temperature sensitivity of TRPV5 and TRPV6 is relatively low. TRPV1-4 are also sensitive to a broad array of endogenous and synthetic ligands. For example, TRPV1 is activated by capsaicin, heat (≥43°C), and many other chemicals, including an endocannabinoid, anandamide; the topical analgesic, camphor; piperine in black pepper; and allicin in garlic (Caterina et al. 1997; Zygmunt et al. 1999; Xu, Blair, and Clapham 2005; McNamara, Randall, and Gunthorpe 2005; Macpherson et al. 2005). Activation of TRPV1 leads to membrane depolarization, and TRPV1-mediated current can be facilitated by extracellular acidification (Xu, Blair, and Clapham 2005). A pH change to <6, ethanol, and nicotine also have similar effects on TRPV1 activity (Trevisani et al. 2002; Liu et al. 2004).
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Another important family within the TRP ion channel superfamily is the transient receptor potential melastatin (TRPM) receptors, composed of eight members. They can be subdivided into four groups, based on structural homology: TRPM1 and 3, TRPM4-5, TRPM6-7, and TRPM2 and 8 [55]. Most of these plasma membrane ion channels are nonselective Ca2+-permeable (TRPM1-3 and TRPM6-8), while TRPM4/5 are Ca2+-impermeable. In addition, TRPM6-7 are Mg2+-permeable and involved in mammalian Mg2+ homeostasis [56]. TRPM members are differently expressed in many tissues, including primary sensory neurons (TRPM3, TRPM8), prostate (TRPM8), pancreatic β–cells (TRPM2, TRPM3, TRPM5), retina cells (TRPM1), kidney (TRPM6), liver, and heart (TRPM4), among others [57]. Unlike the other TRP channels, TRPM channels lack the N-terminal ankyrin repeats.
Glibenclamide as a neuroprotective antidementia drug
Published in Archives of Physiology and Biochemistry, 2022
Alexander Zubov, Zamira Muruzheva, Maria Tikhomirova, Marina Karpenko
In the last decade, it was shown that the SUR1 subunit can interact with the TRPM4 channels (transient receptor potential channel melastatin 4), calcium-activated non-specific cationic channels that are practically impermeable to calcium. TRPM4 channels are present in many body tissues and are expressed in cells of the cardiovascular system, prostate, pancreas, colon, and placenta. In the CNS, SUR1-Kir6.2 channels are expressed in neurons, astrocytes, oligodendrocytes, endothelial cells and microglial cells, and SUR1-TRPM4 are transcriptionally upregulated in those cells after injury or inflammation. (Kurland et al.2016).
An update on the pharmacological management and prevention of cerebral edema: current therapeutic strategies
Published in Expert Opinion on Pharmacotherapy, 2021
Melissa Pergakis, Neeraj Badjatia, J. Marc Simard
SUR1 is inhibited by the sulfonylurea glibenclamide, commonly known as glyburide in the US, originally used to treat diabetes mellitus type II dating back to the 1960s [158]. Glibenclamide is a potent inhibitor of SUR1-TRPM4 channels and has shown efficacy in both animal models of stroke and contusion-TBI. Glibenclamide reduces brain tissue water in rodent models of LHI [52] leading to improved neurological outcomes [137,138,159]. Glibenclamide suppresses contusion expansion in animal models of TBI as well as reduces edema and hemorrhagic progression while improving neurological outcomes [2,146,147].