Da: Cell Signalling Biology Da: Cell Signalling Biology -- Michael J. Berridge Michael J. Berridge --www.cellsignallingbiology.org www.cellsignallingbiology.org -- 2009 2009

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Nella comunicazione chimica il recettore può essere sulla membrana o intracellulare

Michael J. Berridge Michael J. Berridge

Cells are sensitive to an enormous varietyof stimuli. Many of these are chemical innature, such as hormones,neurotransmitters and growth factors. However, cells can also detect other modalities, and this is particularly evidentin sensory cells that are tuned to stimuli such as mechanical deformation (sound and touch), temperature, light and oxygen tension.

Stimuli can be released from cells in many different ways . A number of stimuli, particularly growth factors and cytokines, are carried in vesicles to the cell surface where they appear as a membrane-anchored stimulus that can function as such or is a precursor that is cleaved by proteases such as the ADAM proteases to release the soluble stimulus through a process known as ectodomain shedding . Many stimuli, such as the eicosanoids , nitric oxide and ATP, are formed within the cytoplasm and leave the cell by diffusing across the plasma membrane. In some cases, this exit from the cell is facilitated by special transporters such as the ATP-binding cassette (ABC) transporters. Many stimuli are synthesized as large precursors, such as pro-opiomelanocortin (POMP), which then undergo extensive processing. Many stimuli such as hormones as neurotransmitters are packaged in to vesicles where they are stored before being released by exocytosis. These stimuli then have different modes of action (juxtacrine, autocrin , paracrine and endocrine), which have been defined on the basis of how far they travel to reach their cellular receptor targets.

Michael J. Berridge Michael J. Berridge --

The basic principle of a cell signalling pathway.Stimuli (e.g. hormones, neurotransmitters or growth factors) acting on cell-surface receptors relay information through intracellular signalling pathways that can have a number of components. They usually begin with the activation of transducers that use amplifiers to generate internal messengers that either act locally or can diffuse throughout the cell. These messengers then engage sensors that are coupled to the effectors that are responsible for activating cellular responses. The green and red arrows indicate that cell signalling is a dynamic process consisting of ON mechanisms (green arrows) during which information flows down the pathway, opposed by the OFF mechanisms (red arrows) that switch off the different steps of the signalling pathway.

Michael J. Berridge Michael J. Berridge

Cell stimuli that act through the cyclic AMP signalling pathway.A large number of neurotransmitters and hormones act through G protein-coupled receptors (GPCRs) to engage the cyclic AMP signalling pathway. The GPCR acts through a heterotrimeric G protein, which has α and βγ subunits, to stimulate the amplifier adenylyl cyclase (AC) to generate the second messenger cyclic AMP.

Michael J. Berridge Michael J. Berridge

Cell stimuli that act through the inositol 1,4,5-trisphosphate (InsP3)/diacylglycerol (DAG) signalling pathway.A large number of neurotransmitters and hormones act through G protein-coupled receptors (GPCRs) to engage the InsP3/DAG signalling pathway. The GPCRs that sense these different stimuli all feed into a family of heterotrimeric G proteins, which have α and βγ subunits that stimulate the amplifier phospholipase C (PLC) to generate the two second messengers, InsP3 and DAG.

Le subunità restano ancorate alla membrana.

Ci sono numerose isoforme (isoenzimi) di PKC

Michael J. Berridge Michael J. Berridge

Synthesis and mode of action of the eicosanoids.The eicosanoids are lipid-derived stimuli that are formed from arachidonic acid (AA), which is converted into the prostanoids (green pathway) and the leukotrienes (yellow pathway). The AA is produced by phospholipase A2 (PLA2), which attaches itself to the endoplasmic reticulum where it hydrolyses phospholipids to lysophospholipids with the release of AA. The AA is then metabolized via two separate pathways to produce the prostanoids and leukotrienes. The types of receptors and signalling pathways used by the eicosanoids are shown at the bottom.

Michael J. Berridge Michael J. Berridge

Steroid stimuli operate through genomic or non-genomic mechanisms.The genomic action depends upon steroids passing through the plasma membrane to engage specific receptors that are transcription factors that activate gene transcription. In the non-genomic action, the steroid hormone engages cell-surface receptors to activate conventional signalling pathways.

Stimuli for enzymeStimuli for enzyme--linked receptors linked receptors

Michael J. BerridgeMichael J. Berridge

Growth and survival factors engage enzyme-linked receptors.These single-membrane-spanning receptors have an extracellular ligand-binding domain and an intracellular domain that contains either a tyrosine kinase (TK) or a serine/threonine kinase. The protein tyrosine kinase-linked receptors (PTKRs), which usually function as dimers, assemble a complex of scaffolding proteins (green) and transducers (red) that relay information out to amplifiers that function in different signalling pathways. The serine/threonine kinase-linked receptors (S/TKRs) function as tetramers and have a much simpler signalling pathway in that the serine/threonine kinase functions as both the transducer and amplifier to generate the Smad messengers.

Michael J. BerridgeMichael J. Berridge

Activation of the platelet-derived growth factor receptor (PDGFR).The PDGFR is a typical protein tyrosine kinase-linked receptor. The PDGF dimer binds together two PDGFR monomers, which then phosphorylate each other on multiple tyrosine residues that then provide docking sites for components of a number of prominent signalling pathways.

Michael J. BerridgeMichael J. Berridge

Summary of cytokine signalling pathways.Summary of cytokine signalling pathways.Cytokines and various apoptotic and inflammatory mediators act oCytokines and various apoptotic and inflammatory mediators act on nonn non--enzymeenzyme--containing containing receptors that consist of variable numbers of subunits. Each monreceptors that consist of variable numbers of subunits. Each monomer has a single ransmembrane omer has a single ransmembrane domain with an extracellular liganddomain with an extracellular ligand--binding domain and an inner cytoplasmic domain that lacks binding domain and an inner cytoplasmic domain that lacks enzyme activity but can associate with a number of transducing eenzyme activity but can associate with a number of transducing elements that generate different lements that generate different messengers.messengers. TLR: Toll receptorTLR: Toll receptor

Michael J. BerridgeMichael J. Berridge

The integrin receptor is a heterodimer composed of an α- and a β-subunit. In the absence of stimulation (low-affinity state), the extracellular domains are bent over, but extend out to a high-affinity state following outside-in or inside-out signalling. During the former, the large extracellular domain interacts with various components of either the extracellular matrix (ECM) or cell-surface ligands. Integrins have very short cytoplasmic domains that lack enzyme activity. During receptor activation, the cytoplasmic domain of the β-subunit interacts with transducers such as focal adhesion kinase (FAK), which has tyrosine kinase (TK) activity, enabling an autophosphorylation to create binding sites to activate a number of transducing elements. During inside-out signalling, other receptors activate tyrosine kinases that phosphorylate FAK to induce a high-affinity state that then enables the integrin receptor to bind to other adhesion molecules.

Integrin receptor activation by extracellular matrix (ECM) and cell-surface stimuli.

Michael J. Berridge Michael J. Berridge

Other ion channels, but not Ca2+ channels, can be activated also by iperpolarization

Function of ion channels as receptors for cell stimuli.Function of ion channels as receptors for cell stimuli.Ion channels are sensitive to a range of modalities and can thusIon channels are sensitive to a range of modalities and can thus be considered to be receptors. Unlike other be considered to be receptors. Unlike other receptors, they combine all of the components of the signalling receptors, they combine all of the components of the signalling pathway in a single protein. When they detect pathway in a single protein. When they detect the incoming stimulus (receptor function), they undergo a conforthe incoming stimulus (receptor function), they undergo a conformational change (transducer function) to gate mational change (transducer function) to gate large quantities of ions (amplification function). With regard tlarge quantities of ions (amplification function). With regard to messenger function, those receptors that gate o messenger function, those receptors that gate CaCa2+2+ contribute to Cacontribute to Ca2+2+ signalling pathways (see figure). signalling pathways (see figure). The gating of ions also changes membraneThe gating of ions also changes membranepotential (potential (∆∆VV) and this can have a messenger function by altering the activit) and this can have a messenger function by altering the activity of voltagey of voltage--operated Caoperated Ca2+2+

channels (VOCs).channels (VOCs).

Michael J. BerridgeMichael J. Berridge

The basic mechanism of Ca2+ signalling.The concentration of Ca2+ in cells at rest is approximately 100 nM, but this increases to500 nM or more following a stimulus that activates the Ca2+ ON reactions. When the stimulus is removed, the Ca2+ OFF reactions return the concentration of Ca2+ to its resting level. Ca2+ is a universal signal capable of activating many different cellular processes operating over a very wide time domain.

Michael J. BerridgeMichael J. Berridge

The dynamics of CaThe dynamics of Ca2+2+

signalling.signalling.The dynamics of CaThe dynamics of Ca2+2+ signalling signalling are governed by an interplay are governed by an interplay between the ON and OFF between the ON and OFF reactions that control the reactions that control the fluxes of Cafluxes of Ca2+2+ across both the across both the plasma membrane and the plasma membrane and the internal organelles such as the internal organelles such as the endoplasmic reticulum endoplasmic reticulum (ER) and mitochondria.(ER) and mitochondria.

External stimuli activate the ON reactions, which introduce CaExternal stimuli activate the ON reactions, which introduce Ca2+2+ into the cytoplasm either into the cytoplasm either through channels in the plasma membrane or from internal stores through channels in the plasma membrane or from internal stores such as the ER. Most cells make use of both such as the ER. Most cells make use of both sources, but there are examples of cells using either external osources, but there are examples of cells using either external or internal sources to control specific processes. Mostr internal sources to control specific processes. Mostof the Caof the Ca2+2+ that enters the cytoplasm is adsorbed on to buffers, while a muthat enters the cytoplasm is adsorbed on to buffers, while a much smaller proportion activates the ch smaller proportion activates the effectors to stimulate cellular processes. The OFF reactions remeffectors to stimulate cellular processes. The OFF reactions remove Caove Ca2+2+ from the cytoplasm using a combination from the cytoplasm using a combination of mitochondria and different pumping mechanisms. When cells areof mitochondria and different pumping mechanisms. When cells are at rest, these OFF reactions keep the at rest, these OFF reactions keep the concentration low, but these are temporarily overwhelmed when exconcentration low, but these are temporarily overwhelmed when external stimuli activate the ON reactions. ternal stimuli activate the ON reactions. Sequential activation of the ON and OFF reactions gives rise to Sequential activation of the ON and OFF reactions gives rise to the Cathe Ca2+2+ transients, which are such a characteristictransients, which are such a characteristicfeature of Cafeature of Ca2+2+ signalling systems. PMCA, plasma membrane Casignalling systems. PMCA, plasma membrane Ca2+2+--ATPase; SERCA, sarco/endoATPase; SERCA, sarco/endo--plasmic reticulumplasmic reticulumCaCa2+2+--ATPase. ATPase.

Michael J. BerridgeMichael J. Berridge

Some examples of cell-specific Ca2+ signalling signalsomes.The four cell types represented here generate Ca2+ signals with very different spatial and temporal properties. For example, the skeletal muscle signalsome selects out those components specialized to deliver rapid pulses of Ca2+ to activate contraction, whereas the T cell signalsome has different components that generate the much slower repetitive pulses of Ca2+ necessary to stimulate cell proliferation.

Stretch OC Michael J. BerridgeMichael J. Berridge

Summary of the major components that contribute to the Ca2+ signalling signalsome.A generic Ca2+ signalling signalsome is made up from components of the extensive Ca2+ signalling toolkit. The duplication of the individual components represents the fact that there are numerous isoforms that further enhance the diversity of the Ca2+ signalling systems.

The yellow arrows illustrate the ON reactions that introduce Ca2+ into the cell, and the blue arrows depict the OFF reactions that pump Ca2+ either out of the cell or back into the endoplasmic reticulum (ER). During its passage through the cytoplasm, Ca2+ resides temporarily on the buffers or within the mitochondria. To carry out its signalling function, Ca2+ binds to sensors that then employ a range of effectors to stimulate cellular processes. These different components are mixed and matched to construct Ca2+ modules that are then assembled to produce cell-specific signalsomes. CaBP, Ca2+-binding protein; InsP3R, inositol 1,4,5-trisphosphate receptor; NCX, Na+/Ca2+ exchanger; PLC, phospholipase C; PMCA, plasma membrane Ca2+-ATPase; ROC, receptor-operated channel; RYR, ryanodine receptor; SERCA, sarco/endo-plasmic reticulum Ca2+-ATPase; SMOC, second messenger-operated channel; SOC, store-operated channel; VOC, voltage-operated channel. Stretch OC, Stretch operated channel