Co ur sR SI C Réseaux signalétiques et M1 incidences cellulaires SP RSIC 202 3/2 M1SP 02 4 Co ur Cell signaling sR SI C M1are transmitted via a cascade to Mechanism by which stimuli effector molecules that orchestrate the appropriate response by S P genetic, and structural reprogramming various biochemical, 20 processes 23 / 20 Cellular communication and environmental adaptation 24 Forms of Cell signaling Co ur sR SI C M1 SP 20 23 /20 24 Synaptic Endocrine Direct Co ur of cell signaling pathways Types sR SI C Checkpoint signaling M Stress signaling 1 Lipid signaling SP Morphogen signaling Growth factor signaling signaling 2Hippo 02 Nutrient signaling TOR3signaling / Insulin signaling Integrin2signaling 02 4 Signaling networks and cellular incidence Co ur sR Cell signaling controls various cell functions SI C M1 SP Key biological processes such as cell division, differentiation, growth, and cell-cycle transition specialized cell-specific functions such as neurotransmission, pathogensensing, phagocytosis, antigen-presentation. autophagy and nutrient cycling and recycling. 20 23 /20 24 Co ur Cell Signaling sR SI C Signaling molecules and M their receptors HORMONES 1S RCPG and G protein P Growth factor signaling and their receptors 20 EGF PI3K/TOR Insulin signaling 23 20 Receptors Coupled to Transcription Factors /TGF 24 Co ur Components of Cell Signaling sR SI C M1 SP 20 23 /20 24 How the messages are relayed from the membrane to the nucleus where gene expression, subsequent translations, and protein targeting to the cell membrane and other organelles are triggered. The messages are transferred from the first messenger (ligand) to the receptor, and then decoded with the help of cascades of second messengers (kinases, phosphatases, GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol….). Reception, transduction, response Signaling phases Although there are limited numbers of intracellular messengers, the specificity of the response profiles to the ligands is generated by the involvement of a combination of selected intracellular signaling intermediates. SI C Co ur sR M1 SP 20 23 /20 24 Co urSignaling molecules sR SI C M1 SP 20 23 /20 24 Signals are perturbations of cellular homeostasis , there are different stimuli such as growth factors, hormones, cytokines, neurotransmitters, extracellular matrix components, etc. Mechanical Electrical Chemical, the majority of the signals are chemical in nature Chemical ligands is diverse including small molecules such as lipids (prostaglandins, steroids), proteins (peptide hormones, cytokines, and chemokines, growth factors), complex polymers of sugars (glucan and zymosan), and their combinations (e.g., proteoglycans), nucleic acids…... Co ur sR Soluble lipophilic ligands ligands (small molecules, peptides, and proteins) are polar or sometimes too large and cannot pass through the plasma membrane Most of these ligands bind to the extracellular domain of cellsurface receptors. SI C M1 SP Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors (steroid hormones, thyroid hormones and vitamin D). 20 23 /20 24 Steroid hormones have similar chemical structures to their precursor, cholesterol. Others small ligands (neurotransmitters such as acetylcholine and γaminobutyric acid, and plant hormones such as auxins) Co ur sR NO, due to its small size, diffuses across the plasma membrane and activates pathways regulating vasodilation. SI C But many neurotransmitters are small hydrophilic molecules that bind to ion channels on adjacent cells. M1 SP 20 23 /20 24 Co ur sR Nitric Oxide Signaling Nitric oxide (NO) is a gas that can diffuse directly across the plasma membrane. SI C Due to this property, NO, like steroid hormones, can bind to an intracellular receptor. M1 NO plays an important role regulating blood flow by relaxing smooth muscles around blood vessels (resulting in an increase blood flow). In response to neuronal signaling, NO is released from endothelial cells and binds to its intracellular receptor, guanylyl cyclase (GC), in adjacent smooth muscle cells. SP 20 23 /20 24 Nitric Oxide Signaling Co ur sR SI C Guanylyl Cyclase (GC) is an intracellular receptor for nitric oxide (NO) and an enzyme. M1 When NO is bound to GC, GC convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). SP 20 23 /20 24 cGMP is a necessary secondary messenger in the NO signaling pathway. cGMP can be broken down into guanosine monophosphate (GMP) by enzymes called phosphodiesterases (PDE). Nitric Oxide Signaling Co ur sR In response to neuronal signaling, endothelial cells that wrap around blood vessels produce the small gas Nitric Oxide (NO). SI C NO diffuses out of the endothelial cells and into adjacent smooth muscle cells. Inside the smooth muscle cells, NO binds to its intracellular receptor, guanylyl cyclase (GC). When active, GC metabolizes GTP into the secondary messenger cGMP. M1 SP Increasing levels of cGMP led to the activation of effector proteins, such as myosin light chain kinase, which led to muscle relaxation. As the smoothing muscles around the blood vessels relax, blood flow increases. 20 23 /20 24 The drug Viagra targets phosphodiesters (PDE), enzymes that break down cGMP into GMP. By inhibiting the breakdown of the secondary messenger cGMP, Viagra maintains high cellular levels of cGMP, thus maintaining smooth muscle relaxation, increased blood flow. Co ur Signaling Receptors sR S 2 categories of receptors IC M cell-surface receptors and intracellular 1 Sreceptors. Cell-surface receptors are involved in mostP of the signaling in multicellular organisms. 20 2 3/2 3 categories of cell-surface receptors: 0 24 ion channel receptors G-protein-linked receptors enzyme-linked receptors. Co uIntracellular receptors rs RS IC M1 SP 20 23 Nuclear receptors (for e.g., androgen receptor, estrogen receptor, glucocorticoid receptor, progesterone receptor, retinoic acid receptor thyroid receptor, etc.) hormones, metabolites, or enzymatic ligands, as well as unidentified ligands Cytoplasmic receptors, or organellar receptors like in mitochondria, endoplasmic reticulum, and Golgi apparatus (subcellular compartments) that bind to small lipophilic molecules, which cross the plasma membrane. /20 For example, receptors for glutamate, thyroid hormone, estrogen, and androgens are also present on the mitochondrial membrane. 24 Sigma receptors are found to be associated with the endoplasmic reticulum membrane and act as a chaperone to stabilize ER membrane proteins like IP3 receptor. SI C Co ur sR M1 SP 20 23 /20 24 Co urNuclear receptors NR sR SI C M1 SP 20 23 The NR superfamily over 500 members. divided into 4 classes based on dimerization, DNA binding motifs and specificity, and ligand binding. Steroid Receptors (Class I) also known as nuclear hormone receptors RXR heterodimers (Retinoid X receptor, Class II) Homodimeric orphan receptors (Class III) Monomeric orphan receptors (Class IV) /20 NRs involved in key physiological functions such as cell growth and differentiation, development homeostasis, or metabolism 24 Inappropriate exposure to environmental pollutants, which have the ability to substitute for natural ligands, can cause proliferative, reproductive, and metabolic disorders : hormonedependent cancers, infertility, diabetes, or obesity. Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Co ur sR Dimerization (homo, hetero, or mono) DNA binding (direct repeat or inverted repeat) ligand specificity (required, or not required) SI C M1 Direct Repeat Inverted Repeat SP 20 23 /20 24 C En résumé ou rs R Les récepteurs nucléaires constituent une superfamille dans laquelle on retrouve 4 grandes classes de récepteurs. - SI C Les récepteurs des stéroïdes formés de dimères de glucocorticoïdes, de progestérone, d’œstrogènes M1 SP - Les RXR, rétinoïdes récepteurs qui sont des hétérodimères puisqu’ils vont associer un RXR avec un RAR (acide rétinoïque), un VDR (récepteur à la vitamine D) ou avec un thyroid hormone receptor. 20 23 /20 24 - Les dimeric orphan receptor qui associent deux RXR - Les monomeric orphan receptor qui fonctionnent de façon monomérique Co ur sR N-terminal domain Variable C-terminus DNA-binding domain Hinge region SI C All NR contain a variable N-terminal domain (NTD), a DNA binding domain (DBD), a hinge region, a conserved ligand-binding domain (LBD), a variable C-terminal domain. M1 Ligand-binding domain SP 20 23 /20 24 The 2 most highly conserved domains amongst all NR are DBD and LBD The DBD contains 2 zinc finger motifs, which act as a hook, that allow binding to chromatin within the nucleus. Each class has different DNA binding recognition sequences, which range from variable half-sites with inverted repeats, direct repeats, or no repeats within the DNA sequence Co ur sR Facteur régulateur Fixation de l’Hormone NLS SI C M1 Permet le changement de conformation du R et la dimérisation SP Domaine doigt de zinc domaine (le + conservé) de fixation à l’ADN sur HRE, hormone responsive element 20 23 /20 24 The AF1 and AF2 activation function 1 and 2 contact co-regulatory molecules, but AF-1 is typically a variable ligand-independent (first named transactivation domain. TD) while the AF-2 of the E/F region is liganddependent. NR functional domain organization and most relevant regulatory functions Co ur sR SI C M1 SP 20 23 /20 24 All NR domains undergo post- translational modifications (PTMs), which could regulate protein stability , and multiple domains are involved in interactions with co- regulator proteins (protein– protein interactions (PPI)). As well as proteins that operate in the nucleus, NRs harbour a nuclear localization signal (NLS). Co ur sR The LBD of NR remains highly conserved in function but differs in specificity and affinity to specific ligands. SI C All classes, excluding orphan receptors, are ligand-activated. Ligand binding at the LBD induces an allosteric change, inducing activation. Ligands within each class of nuclear receptors have similar structures. M1 Classes I–III require dimerization within the nucleus while Class IV does not. Class I and III require homodimerization provide stronger zinc finger binding to DNA Class II requires heterodimerization. SP 20 23 /20 24 Class I Class II Co ur sR SI C M1 SP 20 23 /20 24 Class I Co ur sR SI C M1 SP 20 23 /20 24 Schematic model of NR function Class I vs Class II Co ur sR SI C M1 SP Type III receptors reside in the nucleus and exchange bound co-repressors and co-activators. These receptors bind to direct repeat HREs as homodimers. Type IV receptors are almost identical to Type III except they bind HREs that are extended half sites as monomers. 20 23 /20 24 Before ligand binding, type I NRs form inactive complexes with chaperone proteins in the cytoplasm (AR) or in the nucleus (ERs) whereas type II NRs (RXR heterodimers) are bound to their target genes with corepressors. Ligand binding results in the dissociation of chaperone proteins and binding and activation to target genes for type I NRs. Ligand binding results in corepressors release and coactivator recruitment for type II NRs Shematic NR regulation Co ur sR SI C M1 ( A) To activate gene expression, NRs (blue) interact with their DNA response elements. DNA-bound NRs recruit co-activator proteins (magenta), which in turn recruit histone-modifying enzymes. These histone-modifying enzymes are commonly histone acetylases (green), which acetylate histone tails. This modification is a mark of active chromatin. Ultimately, the general transcriptional machinery and RNA Polymerase Pol II (gray) are recruited to drive gene expression. SP 20 23 /20 24 (B) To repress transcription, NRs recruit co-repressor proteins (orange). These proteins recruit other histone deacetylases (red) that reverse histone acetylation and restrict chromatin accessibility. This condensation prevents the transcriptional machinery from accessing the DNA, thus repressing gene expression. Co ur sR Class I SI C M1 SP 20 23 /20 24 Class II Co ur sR SI C M1 SP 20 23 /20 24 Histone acetyletransferase (HAT) and histone deacetylase (HDAC) families. Co ur sR Chromatin conformation according to the HAT/HDAC balance. The acetylation levels of nucleosome histone tails, at lysine residues, are determined through the interplay between acetylation and deacetylation mechanisms engaged respectively through HATs and HDACs enzymes. SI C The different families and classes of enzymes are noted. Ac = Acetyl; CBP = cyclic adenomonophosphate response element-binding (CREB) binding protein; GNAT = Gcn5-related N-acetyltransferases; h GCN5 =human general control of amino acid synthesis protein 5like 2; PCAF = p300/CBP-associated factor; ELP3 = elongation protein 3; MYST = MOZ/YBF2/SAS2/TIP60; TIP60 = TAT interacting proteins 60; TFIIIC90 = transcription factor IIIC 90kDa; TAF1 = TATA Box Binding Protein-Associated Factor, SRC1 = steroid receptor coactivator 1; ACTR = SRC-3, steroid receptor coactivator/AIB-1, M1 SP 20 23 /20 24 Co ur sR Therapeutic target SI C M1 SP 20 23 /20 24 Schematic mechanism of histone acetylation and deacetylation enzymatic control and inhibitors. HAT, histone acetyl transferase; HDAC, histone deacetyl transferase; HDACi, HDAC inhibitors Histone acetyltransferase (HAT) activation as a therapeutic strategy Co ur sR Ac=Acetyl; NFκB=nuclear factor kappa B; UBF-1=upstream binding factor-1; CoAct=coactivator; CoRep=co-repressor; TF=transcription factor; RNApolII=RNA polymerase SI C M1 SP 20 23 /20 24 Co ur sR NR Signaling SI C M1 SP 20 23 /20 24 (B) In a canonical signal-transduction cascade, receptor binding at the plasma membrane initiates enzymatic phosphorylation cascades culminating with transcription factor translocation into the nucleus. (C) Type I steroid nuclear receptors are synthesized in inactive forms associated with heat-shock protein (HSP) complexes in the cytoplasm. Direct hormone binding causes a conformational change, dissociation from HSP complexes and translocation into the nucleus. (D) Type II heterodimeric nuclear receptors bind constitutively to DNA with RXRs as obligate partners. Ligand binding causes a conformational change, dissociation of co-repressor complexes and recruitment of co-activators, such as PGC1a. ESTROGEN RECEPTOR ER Co ur sR SI C M1 SP 20 23 /20 24 The percentage of homology between the different domains The number of amino acids for each receptor Estradiol (E2) mediates numerous phenotypic effects in cells by binding to and activating ERs Genomic Co ur sR ER mechanism of action E2 enters the cell through the lipid membranes and binds ER, which can be present in the cytoplasm and the nucleus. SI C The activated ER forms a dimer to tightly fix chromatin directly at the estrogen-responsive element (ERE) sites or indirectly at activator protein 1 (AP1) or specificity protein 1 (Sp1) sites. ER is then able to remodel chromatin by recruiting cofactors and activating RNA polymerase II (Pol II), at target genes (genomic action). Non Genomic Besides, ERs can use rapid non-genomic action through the interaction with intracellular kinases (mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), . . . ) and the growth factor (GF) receptor GFR) pathways. M1 SP 20 23 /20 24 Co ur sR ER Signaling SI C M1 SP 20 23 /20 24 Co ur sR GPER G-coupled estrogen receptor, E estrogen, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositide 3-kinase, PKA protein kinase A, AKT protein kinase B, EGFR epidermal growth factor receptor, CREB cAMP response element binding protein, CTGF connective growth tissue factor, EGR1 early growth response 1, TF transcription factor. ER Signaling SI C M1 SP 20 23 /20 24 Co ur sR Estrogen metabolites and carcinogensis SI C Simplified diagram demonstrated the effect of estrogen metabolites produced by CYP1B1 in cells including structures (grey field) and processes (cyan field). Blue arrows indicate the direction of the reaction. EM estrogen metabolites, ER estrogen receptor, ROS reactive oxygen species, CYP1B1 cytochrome P450 1B1. M1 SP 20 23 /20 24 Co ur sR Various flavonoids and phytoestrogens either antagonize estrogen synthesis, mimic estrogen activity by binding to the estrogen receptor and activating it or by binding to the ER and preventing ER activation. Genistein, daidzein, equol, miroestrol, deoxymiroestrol, 8phenylnaringenin, coumestrol and resveratrol do not necessarily inhibit nuclear transport of dimerized estrogen receptors, but they do prevent the activation of estrogen-dependent transcription. The Anti-Cancer Charm of Flavonoids: A Cup-of-Tea Will Do! SI C M1 SP 20 23 /20 24 Co ur sR SI C M1 SP ER could also be activated via phosphorylation by growth factor receptor and downstream signaling activation or mutations in its ligand-binding domain, leading to estrogen-independent target gene regulation. In addition, membrane-bound ER crosstalks with growth factor receptor signaling that promotes estrogen-independent tumor growth. Cyclin D is a central transcription target of ER and growth factor receptor signaling pathways, which activates CDK4/6 and induces cell cycle progression from G1 to S phase. Cyclin D/CDK4/6 activation is often associated with endocrine resistance. Classes of drugs in the clinic or in development that inhibit estrogen production, ER function, or degradation, and inhibitors against PI3K, mTOR, or receptor tyrosine kinases are highlighted 20 23 /20 24 Co ur sR Typical heterodimer SI C M1 Typical NR dimer binding to DNA takes place at cognate DNA response elements featuring (imperfect) palindromic sequences or two hexanucleotide half- sites organized as direct, everted or inverted repeats. Typical heterodimers are defined here as the wellcharacterized heterodimers of which both partners contact DNA , sharing RXR as a common protein partner. SP 20 23 /20 24 Examples include pairings with (isoforms of) liver X receptor (LXR), peroxisome proliferator activated receptor (PPAR), pregnane X receptor (PXR), retinoic acid receptor (RAR), retinoid X receptor (RXR), thyroid receptor (TR), vitamin D receptor (VDR) and some orphan receptors. BF3, binding function 3 Co RAR ur The retinoic acid s receptors (RARs) are ligand dependent transcription factors that belong toR the NR1B subtype of the nuclear receptor (NRs) SI superfamily C Mand Roles in development, cell growth survival, vision, spermatogenesis, 1S inflammation, and neural patterning. P These receptors act in trans mainly as heterodimers with retinoid X 2 02 receptors (RXRs). 3 /20 natural The actions of RARs are stimulated by the binding of cognate ligands (all trans retinoic acid) as well as a number of synthetic 24ligands. 3 Retinoic Acid Receptors (RARA, RARB, and RARC), Aberrant RAR signaling leading to cancer : acute promyelocytic leukemia (APL) Co ur sR SI C M1 SP One of the most well-studied examples of aberrant RAR signaling leading to cancer is acute promyelocytic leukemia (APL). It has been shown that APL is the result of a genetic rearrangement of the RARa gene that fuses it to the promyelocytic leukemia gene (PML) or other PMLrelated genes. These PML/RARa fusion proteins lead to dramatic increases in expression of both HDACs and DNA methyltransferases that cause reductions in gene expression for retinoid regulated genes such as those involved in differentiation 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 Co ur sR The benefit of combination therapy to reverse the repression of RARb2 expression in various cancers SI C M1 SP 20 23 /20 24 Normal tissue where RAR/RXRs regulate expression of RARb2 which is vital for the balance between cell proliferation and differentiation and inducing apoptosis when necessary Co ur sR SI C M1 SP 20 23 /20 24 Tumor tissue where hypermethylation of CpG islands on the promoter of RARb2 prevent its expression and in turn repress genes involved in regulation of cellular proliferation and apoptosis leading to the cancer phenotype. Co ur sR SI C M1 SP 20 23 /20 24 Treatment of tumors with combinations of retinoic acid and other inhibitors such as DNA methyltransferase inhibitors (DNMTase inhibitor) that first remove the detrimental hypermethylation and then restore normal expression of RARb2 which is activated by retinoic acids Co ur sR Peroxisome Proliferator-Activated Receptors PPARs superfamily of hormonal nuclear transcription factors 48 members SI C PPARs play an important part in the regulation of energy homeostasis of the body cellular processes (differentiation, proliferation, and apoptosis), immune and inflammatory reactions. Three isoforms of known: PPARα (NR1C1), PPARβ/δ (NR1C2), PPARγ (NR1C3). PPARs are M1 SP 20 23 /20 24 Isoforms of PPARs and their biological effects. Physiological roles of PPARs Co ur sR PPARα) regulates the expression of enzymes that lead to the mobilization of stored fatty acids (FAs) in adipose tissue. SI C M1 expression of fatty acid-catabolizing enzymes in the liver, heart and kidney. Released fatty acids are then oxidized in these tissues to ultimately generate ATP. SP PPARβ/δ is expressed at high levels in the intestine where it mediates the induction of terminal differentiation of epithelium 20 23 /20 24 Activating PPARβ/δ or PPARγ can increase insulin sensitivity, causing improved glucose uptake in diabetic models. PPARβ/δ regulates the expression of fatty acidcatabolizing enzymes in skeletal muscle where released fatty acids are oxidized to generate ATP. PPARγ promotes the differentiation of adipocytes. Co ur sR SI C PPARα, PPARβ/δ and PPARγ can interfere with nuclear factor-κB (NFκB) and AP1 in tissues, including macrophages, endothelial cells, epithelial cells and others, causing the attenuation of pro-inflammatory signalling by decreasing the expression of proinflammatory cytokines, chemokines and cell adhesion molecules, for example, in addition to other trans-repressive mechanisms M1 The activation of PPARα and PPARβ/δ promotes osteoblast activity in bone; whereas, the activation of PPARγ promotes osteoclast activity in bone. SP 20 23 /20 24 C Structure of human ouperoxisome proliferator-activated receptor-α (PPAR-α), -β/δ, and -γ rs RS IC M1 SP 20 23 /20 24 The number inside each domain corresponds to amino acid sequence identity of human PPAR-β/δ and -γ relative to PPAR-α. The numbers above the boxes indicate amino acid positions. DBD, DNA binding domain; LBD, ligand binding domain. Co ur sR Molecular mechanism of action of PPAR-α, -β/δ, and -γ. SI C The PPAR isoforms form heterodimers RXR-α in the presence of their ligands. M1 SP The resultant heterodimer binds to PPAR-response elements (PPRE) in the promoter regions of PPAR-driven genes through DNA-binding domains of PPAR and RXR-α. 20 23 /20 24 Coactivators and co-repressors are essential for modulating the transcription of PPAR target genes, which are involved in many biologic processes PPARs expression in inflammatory bowel disease Co ur sR Ulcerative colitis (UC) provokes inflammation of the colonic intestinal wall, showing decreased expression of PPARs, Crohn's disease (CD) spreads to all layers and sections of the gastrointestinal tract, causing overexpression of PPARs. SI C M1 SP 20 23 /20 24 PPARs expression in inflammatory bowel disease Co ur sR SI C The anti-inflammatory efficacy of PPAR ligands is based on PPAR/RXR-mediated transrepression and/or blockade of the activating phosphorylation and nuclear translocation NF-kB, which finally incurs the transcriptional blockage of inflammatory cytokines, chemokines, and other stress response elements, such as COX2 and iNOS. M1 SP 20 23 /20 24 Co ur sR Key Notes NR are critical for a variety of processes of both physiology and pathology, serving as sensors of stimuli and fine-tuning downstream molecular events that govern complex gene regulatory networks SI C NR dysfunction has been reported in different cancer types for cancer M1 potential therapeutic targets NR ideal targets for cancer therapeutics but the tissue specificity and concomitant resistance for NR–based therapeutics also pose great challenges SP 20 23 /20 24 More recently, a growing number of new-generation NR ligands have been discovered or synthesized that could be both highly efficacious in cancer treatment and with excellent tissue specificity Molecular mechanisms have also been gradually unraveled lately for acquired resistance to NR–based cancer therapeutics, constructive to the development of novel drugs to fight against NR–based therapy resistant Cancers Co Ion channel receptors ur sR SI C M1 SP 20 23 /20 24 Co ur sR ATP Glutamate α-amino-3-hydroxy-5methylisoxazole-4propionic acid N-methyl-D-aspartate SI C M1 SP The largest class of LGICs nicotinic acetylcholine receptors (nAChR), γ-aminobutyric acid (GABA) receptors, 5-hydroxytryptamine-3 (5HT3) receptors, and glycine receptors. The nAChR and 5-HT3R are excitatory receptors, the GABA receptors and glycine receptors are inhibitory receptors 20 23 /20 24 Co ur sR P2X7 receptor The human P2X7 R is a trimeric ligand-gated cation channel coded by the P2XR7 gene (chromosome 12q24) SI C P2X7 is expressed in a wide variety of normal and disease-associated cell types. Activated by extracellular ATP downstream the release of pro-inflammatory mediators, cell proliferation or death, and killing of intracellular pathogens. M1 SP Roles in inflammation, immunity, bone homeostasis, neurological function and neoplasia. 595 amino acids in length 20 23 /20 24 P2X7 receptor including the first (TM1) and second (TM2) transmembrane domains. The relative amount of P2X7 function varies between human individuals due to numerous single nucleotide polymorphisms resulting in either loss- or gain-of-function. Combinations of these polymorphisms give rise to various haplotypes that can also modify P2X7 function. Splice isoforms of the human P2X7 receptor splice isoforms Co ur sR P2X7A full-length P2X7 receptor SI C M1 SP 20 23 /20 24 Splice isoforms can alter receptor expression and function, and modify the signaling properties downstream of receptor activation. Numbered boxes and solid lines represent exons and alternate coding regions respectively. Additional exons, 1’ and N3, present in the introns between exons 1 and 2, and exons 2 and 3 respectively, are termed as originally described. The additional exon inP2X7G and P2X7H introduces a new start codon potentially leading to translation of a P2X7 protein lacking the first transmembrane domain. *To date P2X7K has been observed only in rodents. SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 Co ur sR Enhanced P2X7 receptor expression SI C M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24 SI C Co ur sR M1 SP 20 23 /20 24
