scholarly journals Opening TRPP2 (PKD2L1) requires the transfer of gating charges

2019 ◽  
Vol 116 (31) ◽  
pp. 15540-15549 ◽  
Author(s):  
Leo C. T. Ng ◽  
Thuy N. Vien ◽  
Vladimir Yarov-Yarovoy ◽  
Paul G. DeCaen
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Voltage Gated ◽  
State Dependent ◽  
Transient Receptor ◽  
Voltage Gated Ion Channels ◽  
Gating Charges ◽  
Gated Ion Channels

The opening of voltage-gated ion channels is initiated by transfer of gating charges that sense the electric field across the membrane. Although transient receptor potential ion channels (TRP) are members of this family, their opening is not intrinsically linked to membrane potential, and they are generally not considered voltage gated. Here we demonstrate that TRPP2, a member of the polycystin subfamily of TRP channels encoded by the PKD2L1 gene, is an exception to this rule. TRPP2 borrows a biophysical riff from canonical voltage-gated ion channels, using 2 gating charges found in its fourth transmembrane segment (S4) to control its conductive state. Rosetta structural prediction demonstrates that the S4 undergoes ∼3- to 5-Å transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation–π interactions within the voltage sensor domain (VSD) during membrane depolarization. Our data demonstrate that the transfer of a single gating charge per channel subunit is requisite for voltage, temperature, and osmotic swell polymodal gating of TRPP2. Taken together, we find that irrespective of stimuli, TRPP2 channel opening is dependent on activation of its VSDs.

scholarly journals Structural mechanisms of transient receptor potential ion channels

2020 ◽  
Vol 152 (3) ◽  
Author(s):  
Erhu Cao
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Wide Range ◽  
Human Disorders ◽  
Transient Receptor ◽  
Voltage Gated Ion Channels ◽  
Structural Mechanisms ◽  
Physical And Chemical

Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel TR structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.

Transient receptor potential ion channels as participants in thermosensation and thermoregulation

2007 ◽  
Vol 292 (1) ◽  
pp. R64-R76 ◽  
Author(s):  
Michael J. Caterina
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Core Body Temperature ◽  
Expression Patterns ◽  
Receptor Potential ◽  
Genetic Ablation ◽  
Transient Receptor ◽  
Living Organisms

Living organisms must evaluate changes in environmental and internal temperatures to mount appropriate physiological and behavioral responses conducive to survival. Classical physiology has provided a wealth of information regarding the specialization of thermosensory functions among subclasses of peripheral sensory neurons and intrinsically thermosensitive neurons within the hypothalamus. However, until recently, the molecular mechanisms by which these cells carry out thermometry have remained poorly understood. The demonstration that certain ion channels of the transient receptor potential (TRP) family can be activated by increases or decreases in ambient temperature, along with the recognition of their heterogeneous expression patterns and heterogeneous temperature sensitivities, has led investigators to evaluate these proteins as candidate endogenous thermosensors. Much of this work has involved one specific channel, TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin and related pungent vanilloid compounds and a “heat receptor,” capable of directly depolarizing neurons in response to temperatures >42°C. Evidence for a contribution of TRPV1 to peripheral thermosensation has come from pharmacological, physiological, and genetic approaches. In contrast, although capsaicin-sensitive mechanisms clearly influence core body temperature regulation, the specific contribution of TRPV1 to this process remains a matter of debate. Besides TRPV1, at least six additional thermally sensitive TRP channels have been identified in mammals, and many of these also appear to participate in thermosensation. Moreover, the identification of invertebrate TRP channels, whose genetic ablation alters thermally driven behaviors, makes it clear that thermosensation represents an evolutionarily conserved role of this ion channel family.

scholarly journals Deciphering the interactions of SARS-CoV-2 proteins with human ion channels using machine learning-based method

2021 ◽  
Author(s):  
Nupur S. Munjal ◽  
Dikscha Sapra ◽  
Abhishek Goyal ◽  
K.T. Shreya Parthasarathi ◽  
Akhilesh Pandey ◽  
...  
Keyword(s):  
Machine Learning ◽  
Ion Channels ◽  
Gap Junction ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Cation Channel ◽  
Ppi Networks ◽  
Junction Protein ◽  
Transient Receptor

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the worldwide COVID-19 pandemic which began in 2019. It has a high transmission rate and pathogenicity leading to health emergencies and economic crisis. Recent studies pertaining to the understanding of the molecular pathogenesis of SARS-CoV-2 infection exhibited the indispensable role of ion channels in viral infection inside the host. Moreover, machine learning (ML)-based algorithms are providing higher accuracy for host-SARS-CoV-2 protein-protein interactions (PPIs). In this study, predictions of PPIs of SARS-CoV-2 proteins with human ion channels (HICs) were performed using PPI-MetaGO algorithm. The PPIs were predicted with 82.71% accuracy, 84.09% precision, 84.09% sensitivity, 0.89 AUC-ROC, 65.17% Matthews correlation coefficient (MCC) score and 84.09% F1 score. Thereafter, PPI networks of SARSCoV-2 proteins with HICs were generated. Furthermore, biological pathway analysis of HICs interacting with SARS-CoV-2 proteins showed the involvement of six pathways, namely inflammatory mediator regulation of transient receptor potential (TRP) channels, insulin secretion, renin secretion, gap junction, taste transduction and apelin signaling pathway. Our analysis suggests that transient receptor potential cation channel subfamily M member 4 (TRPM4), transient receptor potential cation channel subfamily A member 1 (TRPA1), gap junction protein alpha 1 (GJA1), potassium calcium-activated channel subfamily N member 4 (KCNN4), acid sensing ion channel subunit 1 (ASIC1) and inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) could serve as an initial set to the experimentalists for further validation. Additionally, various US food and drug administration (FDA) approved drugs interacting with the potential HICs were also identified. The study also reinforcesthe drug repurposing approach for the development of host directed antiviral drugs.

scholarly journals Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hongkang Zhang ◽  
Elaine Reichert ◽  
Adam E Cohen
Keyword(s):  
Ion Channels ◽  
Voltage Clamp ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Inhibitory Effect ◽  
Optical Measurements ◽  
Voltage Gated ◽  
State Dependent ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.

scholarly journals PIRT the TRP Channel Regulating Protein Binds Calmodulin and Cholesterol-Like Ligands

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 478 ◽  
Author(s):  
Nicholas J. Sisco ◽  
Dustin D. Luu ◽  
Minjoo Kim ◽  
Wade D. Van Horn
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Transmembrane Helix ◽  
Receptor Potential ◽  
Outer Leaflet ◽  
Heat Sensor ◽  
Transient Receptor ◽  
Α Helix ◽  
Obesity And Cancer

Transient receptor potential (TRP) ion channels are polymodal receptors that have been implicated in a variety of pathophysiologies, including pain, obesity, and cancer. The capsaicin and heat sensor TRPV1, and the menthol and cold sensor TRPM8, have been shown to be modulated by the membrane protein PIRT (Phosphoinositide-interacting regulator of TRP). The emerging mechanism of PIRT-dependent TRPM8 regulation involves a competitive interaction between PIRT and TRPM8 for the activating phosphatidylinositol 4,5-bisphosphate (PIP2) lipid. As many PIP2 modulated ion channels also interact with calmodulin, we investigated the possible interaction between PIRT and calmodulin. Using microscale thermophoresis (MST), we show that calmodulin binds to the PIRT C-terminal α-helix, which we corroborate with a pull-down experiment, nuclear magnetic resonance-detected binding study, and Rosetta-based computational studies. Furthermore, we identify a cholesterol-recognition amino acid consensus (CRAC) domain in the outer leaflet of the first transmembrane helix of PIRT, and with MST, show that PIRT specifically binds to a number of cholesterol-derivatives. Additional studies identified that PIRT binds to cholecalciferol and oxytocin, which has mechanistic implications for the role of PIRT regulation of additional ion channels. This is the first study to show that PIRT specifically binds to a variety of ligands beyond TRP channels and PIP2.

Transient Receptor Potential (TRP) Channels in the Brain: the Good and the Ugly

2012 ◽  
Vol 20 (3) ◽  
pp. 343-355 ◽  
Author(s):  
Bernd Nilius
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Sensory Function ◽  
Short Paper ◽  
The Novel ◽  
Cellular Functions ◽  
Transient Receptor ◽  
The Brain

The ‘transient receptor potential’ (TRP) multigene family encodes sixspan membrane proteins that function as ion channels in mostly tetrameric structures. Members of this family are conserved from yeast, worm, fly to invertebrate, vertebrate and man. These channels have been stigmatized to function only as cell sensors occupied by sensory function. It turns out that TRP channels fulfil a plethora of cellular functions, including non-sensory functions in our brain. This short paper will highlight the advent of novel ion channels in the brain serving different functions and being significantly involved in the genesis of multiple diseases. We will certainly witness a plethora of the novel roles of this protein family in physiological and pathophysiological functions in our central nervous system.

scholarly journals Dysfunction of transient receptor potential ion channels as an important pathophysiological mechanism in asthma

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Oxana Yu. Kytikova ◽  
Tatyana P. Novgorodtseva ◽  
Yulia K. Denisenko ◽  
Marina V. Antonyuk ◽  
Tatyana A. Gvozdenko
Keyword(s):  
Ion Channels ◽  
Neurogenic Inflammation ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Bronchial Hyperreactivity ◽  
Pathophysiological Mechanism ◽  
Lung Pathology ◽  
Trp Ion Channels ◽  
Transient Receptor

Asthma is a chronic heterogeneous disease characterized by chronic inflammation and bronchial hyperreactivity. Neurogenic inflammation is one of the important causes of hyperreactivity. Dysfunction of transient receptor potential (TRP) ion channels underlies the development of neurogenic inflammation, bronchial hyperreactivity and respiratory symptoms of asthma such as bronchospasm and cough. TRP channels are expressed in the respiratory tract. Their activation is mediated by endogenous and exogenous factors involved in the pathogenesis of asthma. The study of functioning and regulation of TRP channels is relevant, as they could be important therapeutic targets for asthma. The aim of the review is to summarize modern ideas about the mechanisms of functioning and regulation of members of the TRP channel superfamily, the role of which in lung pathology and physiology are the best studied.

scholarly journals TRP Channels Interactome as a Novel Therapeutic Target in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
María Paz Saldías ◽  
Diego Maureira ◽  
Octavio Orellana-Serradell ◽  
Ian Silva ◽  
Boris Lavanderos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ion Channels ◽  
Cancer Progression ◽  
Protein Interactions ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Specific Activity ◽  
Receptor Potential ◽  
Neoplastic Disease ◽  
Transient Receptor

Breast cancer is one of the most frequent cancer types worldwide and the first cause of cancer-related deaths in women. Although significant therapeutic advances have been achieved with drugs such as tamoxifen and trastuzumab, breast cancer still caused 627,000 deaths in 2018. Since cancer is a multifactorial disease, it has become necessary to develop new molecular therapies that can target several relevant cellular processes at once. Ion channels are versatile regulators of several physiological- and pathophysiological-related mechanisms, including cancer-relevant processes such as tumor progression, apoptosis inhibition, proliferation, migration, invasion, and chemoresistance. Ion channels are the main regulators of cellular functions, conducting ions selectively through a pore-forming structure located in the plasma membrane, protein–protein interactions one of their main regulatory mechanisms. Among the different ion channel families, the Transient Receptor Potential (TRP) family stands out in the context of breast cancer since several members have been proposed as prognostic markers in this pathology. However, only a few approaches exist to block their specific activity during tumoral progress. In this article, we describe several TRP channels that have been involved in breast cancer progress with a particular focus on their binding partners that have also been described as drivers of breast cancer progression. Here, we propose disrupting these interactions as attractive and potential new therapeutic targets for treating this neoplastic disease.

scholarly journals Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone

2021 ◽  
Vol 12 ◽  
Author(s):  
William F. Jackson
Keyword(s):  
Blood Pressure ◽  
Ion Channels ◽  
Negative Feedback ◽  
Transient Receptor Potential ◽  
Feedback Regulation ◽  
Receptor Potential ◽  
Myogenic Tone ◽  
Negative Feedback Regulation ◽  
Voltage Gated ◽  
Transient Receptor

Arterioles in the peripheral microcirculation regulate blood flow to and within tissues and organs, control capillary blood pressure and microvascular fluid exchange, govern peripheral vascular resistance, and contribute to the regulation of blood pressure. These important microvessels display pressure-dependent myogenic tone, the steady state level of contractile activity of vascular smooth muscle cells (VSMCs) that sets resting arteriolar internal diameter such that arterioles can both dilate and constrict to meet the blood flow and pressure needs of the tissues and organs that they perfuse. This perspective will focus on the Ca2+-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca2+-dependent negative feedback regulation of myogenic tone is mediated by Ca2+-activated K+ (BKCa) channels and also Ca2+-dependent inactivation of voltage-gated Ca2+ channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca2+-activated Cl− channels (CaCCs; TMEM16A/ANO1), Ca2+-dependent inhibition of voltage-gated K+ (KV) and ATP-sensitive K+ (KATP) channels; and Ca2+-induced-Ca2+ release through inositol 1,4,5-trisphosphate receptors (IP3Rs) participate in Ca2+-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca2+-spark-mediated control of BKCa channel activity, or positive-feedback regulation in cooperation with IP3Rs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca2+ sparklets that activate IP3Rs and intermediate and small conductance Ca2+ activated K+ (IKCa and sKCa) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IP3Rs produce Ca2+ pulsars, Ca2+ wavelets, Ca2+ waves and increased global Ca2+ levels activating EC sKCa and IKCa channels and causing Ca2+-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I2 and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca2+-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.

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