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Signal Transduction and Targeted Therapy Jul 2023Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel... (Review)
Review
Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca, Mg, Na, K, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.
Topics: Animals; Humans; Cations; Mammals; Signal Transduction; Transient Receptor Potential Channels; TRPP Cation Channels
PubMed: 37402746
DOI: 10.1038/s41392-023-01464-x -
International Journal of Molecular... Sep 2023Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca entry through voltage-gated Ca channels (VGCC),...
Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca entry through voltage-gated Ca channels (VGCC), which are classified based on their activation threshold into high- and low-voltage activated channels, expressed specifically for each organ [...].
Topics: Calcium Channels; Calcium-Binding Proteins; Action Potentials
PubMed: 37762560
DOI: 10.3390/ijms241814257 -
JAMA Cardiology Jul 2023A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood.
IMPORTANCE
A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood.
OBJECTIVE
To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy.
DESIGN, SETTING, AND PARTICIPANTS
This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023.
EXPOSURES
The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes.
RESULTS
A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP).
CONCLUSIONS AND RELEVANCE
The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.
Topics: Humans; Female; Pregnancy; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Genome-Wide Association Study; TRPC6 Cation Channel; Placenta; Risk Factors
PubMed: 37285119
DOI: 10.1001/jamacardio.2023.1312 -
ELife Feb 2024Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.
Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.
Topics: Calcium; Hair Cells, Auditory; Calcium Channels; Calcium, Dietary; Hair Cells, Auditory, Inner; Calcium-Binding Proteins
PubMed: 38334748
DOI: 10.7554/eLife.96139 -
Nature Jul 2023Voltage-gated ion channels (VGICs) comprise multiple structural units, the assembly of which is required for function. Structural understanding of how VGIC subunits...
Voltage-gated ion channels (VGICs) comprise multiple structural units, the assembly of which is required for function. Structural understanding of how VGIC subunits assemble and whether chaperone proteins are required is lacking. High-voltage-activated calcium channels (Cas) are paradigmatic multisubunit VGICs whose function and trafficking are powerfully shaped by interactions between pore-forming Ca1 or Ca2 Caα (ref. ), and the auxiliary Caβ and Caαδ subunits. Here we present cryo-electron microscopy structures of human brain and cardiac Ca1.2 bound with Caβ to a chaperone-the endoplasmic reticulum membrane protein complex (EMC)-and of the assembled Ca1.2-Caβ-Caαδ-1 channel. These structures provide a view of an EMC-client complex and define EMC sites-the transmembrane (TM) and cytoplasmic (Cyto) docks; interaction between these sites and the client channel causes partial extraction of a pore subunit and splays open the Caαδ-interaction site. The structures identify the Caαδ-binding site for gabapentinoid anti-pain and anti-anxiety drugs, show that EMC and Caαδ interactions with the channel are mutually exclusive, and indicate that EMC-to-Caαδ hand-off involves a divalent ion-dependent step and Ca1.2 element ordering. Disruption of the EMC-Ca complex compromises Ca function, suggesting that the EMC functions as a channel holdase that facilitates channel assembly. Together, the structures reveal a Ca assembly intermediate and EMC client-binding sites that could have wide-ranging implications for the biogenesis of VGICs and other membrane proteins.
Topics: Humans; Binding Sites; Brain; Calcium Channels, L-Type; Cryoelectron Microscopy; Endoplasmic Reticulum; Gabapentin; Membrane Proteins; Myocardium
PubMed: 37196677
DOI: 10.1038/s41586-023-06175-5 -
Channels (Austin, Tex.) Dec 2023Calcium ions (Ca) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit... (Review)
Review
Calcium ions (Ca) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit information about changes in Ca concentrations to its regulatory targets. CaM plays a critical role in cellular Ca signaling, and interacts with a myriad of target proteins. Ca-dependent modulation by CaM is a major component of a diverse array of processes, ranging from gene expression in neurons to the shaping of the cardiac action potential in heart cells. Furthermore, the protein sequence of CaM is highly evolutionarily conserved, and identical CaM proteins are encoded by three independent genes () in humans. Mutations within any of these three genes may lead to severe cardiac deficits including severe long QT syndrome (LQTS) and/or catecholaminergic polymorphic ventricular tachycardia (CPVT). Research into disease-associated CaM variants has identified several proteins modulated by CaM that are likely to underlie the pathogenesis of these calmodulinopathies, including the cardiac L-type Ca channel (LTCC) Ca1.2, and the sarcoplasmic reticulum Ca release channel, ryanodine receptor 2 (RyR2). Here, we review the research that has been done to identify calmodulinopathic CaM mutations and evaluate the mechanisms underlying their role in disease.
Topics: Humans; Calmodulin; Mutation; Tachycardia, Ventricular; Long QT Syndrome; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Calcium
PubMed: 36629534
DOI: 10.1080/19336950.2023.2165278