cell signaling

Cells, whether unicellular organisms or cells within multicellular organisms, adjust to signals within their environment and communicate with other cells.

▼ autocrine : cellular responses : combinatorial : contact-dependent signaling : cytokines : delay/rapidity : distance of signal : endocrine : environmental signals : evolution : histidine kinase : hormones : neuronal signaling : neurotransmitters : paracrine : prokaryote signaling : rapidity/delay : receptor proteins : receptors : regulator proteins : SH domains : signal termination : signaling distance : signal transduction ▼

Receptors are molecules that receive signals by binding ligands, for which receptors have varying binding affinity. Signal transduction is the process of converting signals from one form to another, ultimately adjusting an intracellular process, as in metabolic regulation, or an intranuclear process, such as gene expression.

Signaling operates at various distances:
● contact signaling – particularly important in immune signaling and during development

signaling mediated by synthesized signal mediators
● autocrine – chemical mediators (cytokines, growth factors) that operate on the cell that produces the mediator [1, 2]

signaling mediated by secreted signal mediators
● paracrine – short-range
● endocrine – long-range via hormones

Neurons signal at long-range by virtue of their long axonal processes, but neurotransmitters released into the synaptic cleft operate at short-range, enabling rapid, precise signaling.

Speed of signaling is determined by:
● speed of production of the signal (synthesis of mediators)
● speed of delivery of signal mediators (delivery of mediators to target cells)
● speed of cellular response to the signal
● depolarization, impulse propagation, repolarization of nerve cells

Signals are terminated by:
● dissociation of mediator ligand from receptor
● absorption of mediator by neighboring target cells (neurotransmitters and other paracrine mediators)
● enzymatic destruction of mediators
● immobilization by adsorption of mediators in ECM or by binding to intracellular proteins

Signal transduction is usually performed by enzymes in association with second messengers. Signaling proteins operate in a combinatorial fashion within signaling networks, greatly extending the biological roles of individual proteins. The simplest such system comprises two components – a histidine kinase protein that receives a signal and transmits it, via phosphorelay, to a partner response-regulator protein. Protein domains and motif interactions display considerable flexibility, providing an obvious evolutionary advantage. For example, single amino acid substitutions alter the binding specificity of SH2 domains such that specificity can change quite rapidly, enabling formation of new signaling connections as metazoan organisms became more complex.

Environmental signals include mechanical stimuli (light, sound) and chemical stimuli. The origin of a biochemical stimulus may be the cell itself (autocrine), adjacent cells (paracrine), the plasma membrane of adjacent cells (contact inhibition), or distant cells (endocrine).

Neurotransmission incorporates interaction between neurotransmitters and specific receptor proteins. Cytokines mediate paracrine stimulation, and hormones mediate endocrine stimulation.

Cellular responses to signaling include:
● alterations in gene expression (transcription)
● alteration of electrophysiological charge
● cellular cycling and reproduction
● regulation of cellular metabolic processes
● biosynthesis with or without secretion
● cellular growth
● chemotaxis, migration, and, in multicellular organisms, extravasation
● initiation of immune and inflammatory responses
● differentiation into cell lines or maturation of cell lines
● cellular survival or apoptosis

Intracellular interactions in prokaryotes
Four kinds of cell interactions can be distinguished:
1) Transfer of a chemical signal from one cell to another. The variety of such transfers is presented in several examples.
2) Signaling by direct physical contact between two cell bodies, which may involve their surfaces or cell appendages, such as fibrils, pili, or flagella (bacterial flagella). Direct physical contact is often involved in cell swarming.
3) Syntrophic metabolism. Schink Syntrophism Among Prokaryotes.
4) Gene transfer from one cell to another.


• bacterial interactions • concentration gradients • ion channels • protein pumps • receptor proteins • receptor-mediated endocytosis • GPCRs • GPCR families • hormones • neurotransmission • Nitric Oxide • neuronal interconnections • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • signaling gradients :

KEGG Encyclopedia : Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) : Orthology Transporters (+diseases) : Orthology Two-component system : Orthology Receptors and channels (+diseases) : Orthology Cytokines :
Orthology Cell adhesion molecules (CAMs) : Orthology CAM ligands : Orthology CD molecules :
Orthology GTP-binding proteins :

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cell-surface receptors

Receptors on cell-surfaces participate in intercellular signaling by transducing conformational change, which is induced in the receptor upon ligand-binding, into intracellular signaling and altered biophysiological activity. Thousands of receptors of varying specificity for activating ligands participate in the fine-tuned network of signaling cascades that is essential for biological functioning.

This bewildering array of receptors is variably classified according to ligand, receptor, or pathway and includes the largest protein family known (GPCRs).

Broadly, surface receptors responsive to hormones are divided into indirect-enzymatic metabotropic receptors and direct-ion channel, ionotropic receptors.

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GPCR

Guanine nucleotide-binding protein-coupled receptors, G-protein coupled receptors, GPCRs, serpentine receptors, 7TM receptors, or heptahelical receptors are a large family of protein receptors in which an intracellular G-protein is coupled to a transmembrane receptor.

▼ alpha-helices : cascade : effector enzymes : evolution : families : functions : GABA receptors : GDP/GTP : G-proteins : inorganic stimuli : opioid receptor : PDZ domains : phylogeny : physical stimuli : second messengers : stimuli : transmembrane receptors : trimeric ▼

GPCRs transduce signals from transmembrane receptors for sensory, hormonal, chemical, or photic stimuli into regulation of effector enzymes and ion channels, chemotaxis, and cellular signal transduction. GPCRs are diverse and of ancient unicellular evolutionary origin, and are found in fungi, plants, and animals. Sequence similarities of 7TM receptors, which stem from phylogenetic relatedness, are confined largely to the transmembrane domains. They share a common structure of plasma membrane-spanning helices with seven hydrophobic domains (7-TMSs). GPCRs are typically 20-28 amino acid residues long.

GPCRs are trimeric proteins that respond to a variety of specific ligands and stimuli – for example, photons, ions, biogenic amines, nucleosides, lipids, amino acids, and peptides. GPCRs are the only non-ion-channel plasma membrane receptors that are activated by inorganic chemicals and physical stimuli. Transmembrane GPCRs bind GDP when inactive, and switch the bound nucleotide to GTP when activated. Although most GPCRs do not require dimerization for their function, some receptors such as the gamma-amino butyric acid (GABA) receptors require heterodimerization of paralogs for their proper expression and function. [r]

The signalling cascade begins with attachment of a specific ligand, signaling molecule, neurotransmitter, cellular adhesion molecule, hormone, steroid, cytokine, or a specific energetic stimulus, which initiates brief (seconds) binding of GTP rather than GDP. Signal transduction is accomplished through the coupling of G-proteins, via second messengers, to various secondary pathways involving ion channels, adenylyl cyclases, and phospholipases. Further, GPCRs may also couple to other proteins, such as those containing PDZ domains. Second messengers include adenosine 3',5'-monophosphate (cAMP), cGMP, phosphoinositides, diacylglycerol (DAG), and calcium ions. Triggered events include activation of kinase cascades and phosphorylation of cytosolic factors and nuclear transcriptional factors. Activated GPCRs also recruit GPCR receptor kinases (GRKs) that phosphorylate the receptors themselves to facilitate termination of signaling or receptor turnover.

GPCR functions include:
a) generation of second messengers including cGMP and IP3, which stimulate phosphorylation reactions, causing release of second-messenger calcium ions from storage in ER,
b) generation of cAMP and activation of the transcription factor, cAMP response element binding protein (CREB) to stimulate gene transcription
c) cellular signal transduction
d) regulation of gene transcription
e) chemotaxis
f) ion channel opening (confromational change) in response to neurotransmitters

: animation G-protein : Tables Second Messengers  Cell signaling  RTKs :

It is anticipated that future elucidation of GPCR constitution will reveal alpha-helical structures, consisting of 20 to 28 amino acids each.

On-line structural representations for the human µ opioid receptor, for example, is available as a 2D schematic. The 3D structure for inactive (dark) rhodopsin has been established, and the GPCRDB server holds atomic coordinates of 3D models of GPCRs. For more detailed information on-line about GPCRs, consult the GPCR database at GPCRDB.

The GPCRs have been divided into at least six families of GPCRs showing little to no sequence similarity, which can not be traced to a single evolutionary origin.

Tables  Cell signaling  Receptor Tyrosine Kinases(RTK) :

• CELL SIGNALING ~ ERKs • GPCRs • GPCR families • hormones • Nitric Oxide• neurotransmission • neuronal interconnections ~ PKA, protein kinase A ~ PKC ~ protein kinase A ~ protein kinase C ~ protein tyrosine kinases • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs)  Cell signaling • signaling gradients • signal transduction • two-component systems • animation MAPK signal transduction : animation G-protein :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :

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immune signaling

In cells of the immune system, signaling leads to activation of cell-type specific immune activities. Ligand interaction with receptors on the surface of cells of the immune system triggers intracellular signal transduction directly or through association with assistant signal transduction molecules (CD3, IgαIgβ, etc.).

Cytokines are secreted by immune cells in response to cellular signaling, and bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Interleukins comprise the largest class of cytokines, and are manufactured by one leukocyte to act on other leukocytes as signaling ligands. Cytokines are often produced in cascades.
Cytokine receptors:
● Hematopoietin family receptors
___ ● Colony-stimulating factors (CSFs)
● Interferon family receptors
● Tumor Necrosis Factor family receptors
● Chemokine family receptors

Phagocytic cells of the innate immune response employ:
● Fc receptors (FcR, Ig-Fc)
● Complement receptors
● Scavenger receptors
● Toll-like receptors
__ ● adaptor proteins with TIR domains

Activation of lymphocytes signaling of the adaptive immune response requires:
● lymphocyte receptors, associated with
● ITAM-bearing signal transduction molecules, and
● CD45
● adaptor proteins
● second messengers

Immune signaling serves a variety of functions:
● Pre-peripheral-antigen binding
_ ● apoptotic deletion of cells bearing receptors against self-peptides
● Post-peripheral-antigen binding
_ ● activation of immune and inflammatory response activities
__ ● secretion of immune mediator molecules – acute phase components, antibodies, ingestion, disgestion, externalization, and presentation of fragmented antigen (epitope peptide), complement components, cytokines, eicosanoids (prostaglandins and leukotrienes), kinins
__ ● production of inhibitory molecules, such as IκB that regulate immune activity
__ ● surface expression of cell-type specific markers and receptors
__ ● expression of surface receptors fine-tuned by somatic hypermutation
__ ● activation of clonal expansion by entry into cell cycle and proliferation
__ ● activation of cellular differentiation from precursor to committed cell lines
__ ● activation of cellular maturation from cell line to specialized cells
__ ● cellular survival responses
__ ● chemotaxis, migration, and leukocyte adhesion cascade

Signaling in the innate immune response :

Pattern recognition receptors (PRR) are a class of innate immune response-expressed proteins that respond to pathogen-associated molecular patterns (PAMP) and endogenous stress signals termed danger-associated molecular patterns (DAMP). The evolutionarily more recent adaptive immune response employs diverse surface receptors that display decremental binding affinities for epitope stimuli.

Pattern recognition receptors include:
● Membrane-associated PRR
_____ ● Toll-like receptors (TLR) that sense pathogen-associated or damage-associated molecular patterns. In Drosphila, Toll and immunodeficiency (Imd) receptors may link innate and adaptive immune responses (Fig), responding to bacterial and fungal pathogens and activating NF-κB homologs (Dif, dorsal and Relish), thus driving antimicrobial peptide gene expression.[ffta]
● Cytoplasmic PRR
● Secreted PRR, including complement receptors

Toll-like receptors (TLRs) appear to be one of the most ancient, conserved components of the immune system, and are the basic signaling receptors of the innate immune system. TLRs are activated by molecules associated with pathogens (PAMPs) or with injured host cells/tissue (DAMPs). Most identified TLR ligands are either conserved microbial products that signal the presence of an infection, or endogenous ligands resulting from other danger conditions. TLRs trigger signals evoking synthesis and secretion of cytokines and activation of host defenses through NF-κB, MAP kinases, and costimulatory molecules.

The TLR family is characterized by the presence of leucine-rich repeats, which mediate ligand binding, and co-receptors with the Toll/interleukin-1 receptor-like domain (TIR), which mediate interaction with intracellular signaling proteins. To avoid excessive inflammatory responses, TLR signalling must be tightly regulated. MAPK phosphatase 1 (MKP1) is a key negative regulator of Toll-like receptor (TLR)-induced inflammation in vivo. Phosphorylation of MAPK p38 — which is associated with the modulation of cytokine production — is considerably increased and prolonged in the absence of MKP1. [MKP1]
Table  Toll-like Receptors

NF-κBs, Nuclear Factor kappa Bs, are ubiquitous transcription factors involved in responses to cellular stressors such as cytokines, bacterial antigens, and viral antigens. Free NF-κB translocates to the nucleus where it binds to specific κB sequences in DNA, initiating transcription of related genes, including those for immunoreceptors, cytokines, and its own inhibitor, IκB. Inhibitor of kappa B (IκB, IkappaBalpha) inactivates NF-κB by sequestering NF-κB dimers within the cytoplasm. Physiological activities mediated by NF-κB include cellular proliferation, and inflammatory, immune, and cellular survival responses.
[] signaling pathways []

Signaling in the adaptive immune response :

Antigens act as ligands for BCR, while epitope peptide•MHC complexes act as ligands for TCR. Hematopoietic growth factors stimulate cell division in immune and blood cell lines.

Signal transduction molecules:
Because both BCR and TCR have very short cytoplasmic domains, they must associate with invariant signal transduction molecules in order to generate an intracellular signal (IgαIgβ for BCR, CD3 for TCR). The antigen-specific receptors and signal transduction molecules cluster together in the plasma membrane, and signaling is effected by long ITAM-containing cytoplasmic domains on the signal transduction molecules. ITAMs are immunoreceptor tyrosine-based activation motifs that are phosphorylated by src-family protein tyrosine kinase enzymes (PTK). Protein kinases add phosphate groups to tyrosine (or serine or threonine) residues of other proteins, often those of enzymes. Phosphatases remove the phosphate groups, reversing the effects of protein kinases. Phospholipases such as PLC cleave specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances. Phospholipase C-γ cleaves the membrane phospholipid, phosphatidylinositol bisphosphate (PIP2) into the signaling molecules, inositol trisphosphate (IP3) and diacylglycerol (DAG).

Phosphorylation can activate or inactivate enzymes, or can create binding sites that lead to increased concentration of cytoplasmic proteins (and hence their accessibilty for phosphorylation). Activation of lymphocytes also requires CD45 (common leukocyte antigen), which is necessory for receptor-mediated activation of lymphocytes.

Phosphorylated ITAMs can bind to other PTKs (Syk for B cells, ZAP-70 for T cells), triggering a cascade of cytoplasmic enzymes or second messengers, such as calcium ions, diacylglycerol, G-proteins, IP3, MAP kinases, PKCs, and transcription factors, such as NF-κB. Ultimately, gene expression via transcription of mRNA leads to immune activities.

Tables  Apoptosis vs Necrosis  Apoptosis  Cell Adhesion Molecules  Cell signaling  Complement Receptors  Cytokines  Eicosanoid Actions  Fc receptors  Immunoglobulins  Interferons  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers  Scavenger Receptors  Toll-like Receptors

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intracellular receptors

While a large number of cell-surface receptors are employed in receiving environmental signals, fine-tuning of intracellular signaling relies upon a larger number of intracellular receptors and 'signaling' enzymes.

Location of intracellular receptors
● nucleus
● endoplasmic reticulum
● cytoplasm
● intracellular vesicles [s]

Families include receptors/for :
● constitutive androstane receptor (CAR, nuclear receptor subfamily 1, group I, member 3, NR1I3)
● farnesoid X receptor (FXR, nuclear receptor subfamily 1, group H, member 4, NR1H4)
● IP3 receptor (inositol triphosphate, IP3, inositol 1,4,5-triphosphate receptor, type 1, ITPR1)
● liver X receptor
● peroxisome proliferator-activated receptors (PPARs, α, γ and δ)
● pregnane X receptor
● retinoic acid receptor (RARA)
● retinoid X receptor (RXRA)
● sigma1 (neurosteroids)
● steroid and sex hormones
● thyroid hormone (α and β)

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neuronal interconnections

The neuron is the basic operating unit of the central nervous system. Inter-neuronal information processing, involving complex neural networks, provides the nervous system with its enormous functional capacity. The human brain contains about 10^(11) neurons*, which connect, via synapses, with an average of 1000 other neurons. In total, the human brain may contain somewhere between 10^(14) and 10^(15) synaptic connections. Neurotransmitter chemicals effect the connection between neurons, when they cross the gap between neurons and interact with specific receptor proteins. More than one hundred chemicals and a much larger number of receptors have been implicated in synaptic transmission. Some neurotransmitters are the targets of drug therapies. Receptor molecules are the targets of neurotoxic venomous substances.* 10^(11) is equivalent to a 10 followed by 11 zeros = 1,000,000,000,000

Depolarization of neuronal cell membranes beyond a necessary threshold results in action potentials which propagate along the soma/axon/dendrite to the pre-synaptic terminal bulb. At the pre-synaptic terminal, the wave of depolarization results in release of vesicle-stored neurotransmitters into the synaptic cleft. Released neurotransmitters bind to specific post-synaptic receptors that open ion channels, resulting in further depolarization and post-synaptic action potentials.

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signal transduction

Cellular signal transduction involves the conversion of one signal or stimulus (mechanical or chemical) to another. The transduction process is usually performed by enzymes in association with second messengers.

▼ : 7TM receptors : classes of receptors : controlled activities : coupling : DAG : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs : heptahelical receptors : hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands : phospholipases : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP : receptor classes : serpentine receptors : targets for control : 7TM receptors : ▼

Extracellular signals impinge upon specialized membranous receptors. Sensory transduction involves the conversion of mechanical or chemical stimuli to cellular signals or neurophysiological signals. Intracellular signals enable communication within cells, while intercellular signals enable communication between cells.

Tables  Cell Adhesion Molecules  Cell signaling  Immune Cytokines  Receptor Tyrosine Kinases (RTKs)  Second Messengers 

Chemical signals (ligands) include :
1. neurotransmitters : acetylcholine, dopamine, epinephrine, GABA, glycine, norepinephrine, serotonin (5HT), etc.
2. hormones
3. phospholipids
4. growth factors
5. nutrients

Classes of receptors:
1. Membrane-penetrating receptors possessing/connected to intrinsic enzymatic activity:
…….a) receptor tyrosine kinases (RTKs) capable of autophosphorylation as well as phosphorylation of other substrates (incl. EGF, FGF, insulin, PDGF receptors),
…….b) tyrosine phosphatases (CD45),
…….c) guanylate cyclases (natriuretic peptide receptors),
…….d) serine/threonine kinases (activins, inhibins, bone morphogenetic proteins (BMPs), TGF-beta receptors).
…….e) receptors coupled to intracellular tyrosine kinases by direct protein-protein interactions: 'Multiprotein signaling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.'[s].

Phospholipases and phospholipids participate in transmission of ligand-receptor induced signals from the plasma membrane to intracellular proteins, primarily PKC, which is maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. PI-3K is tyrosine phosphorylated and activated by various RTKs and receptor-associated PTKs. PI-3K is activated by the PDGF, EGF, insulin, IGF-1, HGF and NGF receptors. The p85 subunit of PI-3K is activated by tyrosine phosphorylation, but only the 110 kDa subunit is enzymatically active.

Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular DAG and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions (PKC is maximally active in the presence of second messengers, calcium ions and diacylglycerol).

Diacylglycerol (DAG) is an intracellular messenger, which accumulates transiently in cells exposed to growth factors or other stimuli. Cellular responses such as growth and differentiation are impacted by the binding of DAG to PKC, thus activating PKC. Diacylglycerol kinases (DGKs) are responsible for eliminating the function of diacylglycerol (DAG) and for producing phosphatidic acid (PA) (both molecules are connected to cancer).

DGKzeta regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases (DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

2. Serpentine receptors, guanine nucleotide-binding protein-coupled receptors, or GPCRs, in which a characteristic trans-membrane structure spans the cell membrane seven times. Intracellular signalling is carried out by association of the neurotransmitter with G-proteins (small GTP-binding and hydrolyzing proteins), which leads to generation of second messengers. GTP-hydrolytic activity of G-proteins is regulated by GTPase activating proteins, GAPs. Ras, is a proto-oncogenic G-protein involved in carcinogenesis. Other cancer-active G-proteins include the gene products of the neurofibromatosis type-1 (NF1) susceptibility locus and the BCR locus (break point cluster region gene).

There are several families of GPCRs, including:
(a) GPCRs that modulate adenylate cyclase activity
(b) GPCRs that activate phospholipase C-gamma, leading to hydrolysis of polyphosphoinositides (such as PIP2) and generating the second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3). This class of receptors includes receptors for angiotensin, bradykinin and vasopressin.
(c) Photoreceptors coupled to a G-protein (transducin) that activates a phosphodiesterase, depressing the level of second messenger cGMP. The drop in cGMP causes closing of a Na+/Ca2+ ion channel, leading to hyperpolarization of the cell.

3. Intracellular receptors that migrate to the nucleus after binding to the ligand – here the ligand-receptor complex directly affects gene transcription. Hormone receptors are cytoplasmic proteins that bypass membrane-bound signal transduction pathways – receptors for lipophilic steroid/thyroid hormones, the glucocorticoid, vitamin D, retinoic acid and thyroid hormones. All hormone receptors are capable both of binding hormone and of directly activating gene transcription (bi-directional). After binding the hormonal ligand, the hormone-receptor complex translocates to the nucleus and binds to specific DNA sequences (hormone response elements, HREs), resulting in altered transcription rates of the associated gene.

Coupling of ligand-receptor interactions to intracellular events
1. phosphorylations by tyrosine kinases and/or serine/threonine kinases – two-component systems

Intracellular events controlled by signaling:
1. gene expression (transcription)
2. chemotaxis
3. cellular growth, proliferation, and differentiation (tyrosine and serine/threonine phosphorylation)

Protein kinases are targetted by pharmaceuticals because PKs play a variety of roles in disease states. Kinase inhibitors bind to the kinase in at least four different binding modes:
(1) direct competition with ATP at the ATP binding site;
(2) engagement of an adjacent allosteric binding site in the ATP pocket, which is usually accessible when the activation loop is in the inactive conformation; and
(3) binding at sites remote from the ATP site (but still close to the ATP) that impact kinase activity;
(4) binding outside of the ATP binding pocket (truly allosteric).

Kinases can escape inhibition by mutating key residues in their catalytic domain, thus becoming resistant to the kinase inhibitors. Those kinase that have or gain functional mutations may be more sensitive or resistant to inhibition by kinase inhibitors than is the wt form of the kinase.

▲: 7TM receptors סּ adhesion סּ cell membranes סּ chemotaxis : classes of receptors : controlled activities : coupling : DAG ~ DAG ~ DAGKs ~ diacylglycerol ~ diacyl glycerol kinase : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs סּ GPCRs סּ GPCR families s : heptahelical receptors סּ hormones: hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands סּ microtubules סּ migration ₪ molecular switches סּ neurotransmission סּ neuronal interconnections : phospholipases ~ phospholipase C-gamma : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP ¤ Ras : receptor classes סּ receptor-mediated endocytosis סּ receptor proteins : serpentine receptors ~ signaling items ¤ signaling molecules : targets for control : 7TM receptors : ▲

Chemotaxis • GPCRs • GPCR families • hormones • neurotransmission • Nitric Oxide • neuronal interconnections • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs) Tables  Cell signaling  Cell Adhesion  Second Messengers  Immune Cytokines  Apoptosis vs Necrosis  Apoptosis  Malignant Transformation  Oncogenes Proto-oncogenes  Regulatory Proteins Sequences  • signaling gradients • two-component systems • animation MAPK signal transduction : more :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) : Orthology Transporters (+diseases) : Orthology Two-component system : Orthology Receptors and channels (+diseases) : Orthology Cytokines : Orthology Cell adhesion molecules (CAMs) : Orthology CAM ligands : Orthology CD molecules : Orthology GTP-binding proteins :

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