r r r Cell Signalling Biology Michael J. Berridge Module 1 Introduction 1 1 Module 1 Introduction The aim of this website is to describe cell signalling within mitter, hormone or growth factor), which then alters the its biological context. There has been an explosion in the activity of target cells. The latter have receptors capable of characterization of signalling components and pathways. detecting the incoming signal and transferring the inform- The next major challenge is to understand how cells exploit ation to the appropriate internal cell signalling pathway to this large signalling toolkit to assemble the specific sig- bring about a change in cellular activity. nalling pathways they require to communicate with each other. The primary focus is the biology of cell signalling. Communication through electrical The emerging information on cell signalling pathways is signals integrated and presented within the context of specific cell Communication through electrical signals is found mainly types and processes. The beauty of cell signalling is the in excitable systems, particularly in the heart and brain. It way different pathways are combined and adapted to con- is usually fast and requires the cells to be coupled together trol a diverse array of cellular processes in widely different through low-resistance pathways such as the gap junc- spatial and temporal domains. tions (Module 1: Figure cell communication). In addition The first half of the website characterizes the compon- to passing electrical charge, the pores in these gap junctions ents and properties of the major cell signalling pathways, are large enough for low-molecular-mass molecules such with special emphasis on how they are switched on and as metabolites and second messengers to diffuse from one off. Attention is also focused on the spatial and temporal cell to another. aspects that determine how information is encoded and distributed to precise cellular locations. The second half of the website deals with the way these different signalling Communication through chemical pathways are employed to control the life history of cells signals from their birth during the process of cell proliferation, Cells are enclosed within a lipophilic plasma membrane, their differentiation into specific cell types to carry out which represents a formidable barrier that has to be crossed different cell functions, and finally their death through by all incoming signals. Hydrophobic hormones, such as processes such as apoptosis. Cell signalling orchestrates the steroid hormones, can simply diffuse across this cell- all these cellular processes. Many of the same signalling surface barrier to gain access to protein receptors located in systems that control development come into play again to either the cytoplasm or the nucleus. More elaborate mech- regulate a wide range of specific processes in adult cells, anisms are required for the water-soluble stimuli (e.g. hor- such as contraction, secretion, metabolism, proliferation, mones, neurotransmitters and growth factors) that cannot information processing in neurons and sensory perception. cross the plasma membrane (Module 1: Figure cell com- These examples illustrate how cell signalling pathways are munication). The basic concept of a cell signalling path- adapted and co-ordinated to regulate many different cellu- way, therefore, concerns the mechanisms responsible for lar processes. This intimate relationship between cell sig- receiving this external information and relaying it through nalling and biology is providing valuable insights into the internal cell signalling pathways to activate the sensor and underlying genetic and phenotypic defects responsible for effector mechanisms that bring about a change in cellular many of the major human diseases. responses (Module 1: Figure cell signalling mechanism). Cell signalling is a dynamic process in that there are ON Overview of cell signalling mechanisms mechanisms during which information flows down the sig- Cells in organisms such as us constantly communicate with nalling pathway in response to external stimuli (the green each other. This cellular discourse occurs through both arrows in Module 1: Figure cell signalling mechanism), electrical and chemical signals (Module 1: Figure cell com- opposed by the OFF mechanisms that are responsible for munication). Communication through electrical signals is switching off the signalling system once external stimuli very fast and depends upon the presence of gap junctions are withdrawn (the red arrows in Module 1: Figure cell to allow information to pass directly from one cell to its signalling mechanism). Some of these basic principles of neighbour. Communication through chemical signals is by cell signalling are explored in this introductory module, far the major form of information transfer between cells. which will also briefly outline the contents of the other One cell releases a chemical stimulus (e.g. a neurotrans- modules. Green text indicates links to content within this module; blue text ON mechanisms indicates links to content in other modules Most signalling pathways begin with the arrival of external Please cite as Berridge, M.J. (2012) Cell Signalling Biology; cell stimuli usually in the form of a chemical signal, which doi:10.1042/csb0001001 is received by receptors at the cell periphery that function C 2012 Portland Press Limited www.cellsignallingbiology.org Licensed copy. Copying is not permitted, except with prior permission and as allowed by law. r r r Cell Signalling Biology Michael J. Berridge Module 1 Introduction 1 2 Module 1: Figure cell communication CHEMICAL ELECTRICAL COMMUNICATION COMMUNICATION Stimulus (e.g. Hormone, neurotransmitter, Gap junction growth factor) Receptor Cell signalling pathway Enucl Ecyto Ecyto Cell communication through electrical and chemical signalling mechanisms. Cells that are connected through the low-resistance gap junctions (shown on the left) can communicate rapidly with each other by passing electrical current or through the diffusion of low-molecular-mass second messengers such as cyclic AMP and inositol 1,4,5-trisphosphate (InsP3). In the case of chemical communication (shown on the right), one cell releases a stimulus, which diffuses to a target cell that has receptors to detect the stimulus and to relay information along various cell signalling pathways to activate effectors either in the nucleus (Enucl)orcytoplasm(Ecyto). Module 1: Figure cell signalling mechanism STIMULI Receptors Transducers Amplifiers Signalling Messengers pathway Sensors and effectors CELLULAR RESPONSES Fertilization Learning and memory Cell proliferation Membrane excitability Cell differentiation Metabolism Secretion Contraction 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. as molecular antennae embedded in the plasma membrane messengers. These messengers stimulate the sensors and ef- (Module 1: Figure cell signalling mechanism). These re- fectors responsible for activating cellular responses. These ceptors then function to transfer information to a vari- ON mechanisms responsible for transmitting information ety of transducers and amplifiers to produce intracellular into the cell are counteracted by the OFF mechanisms that C 2012 Portland Press Limited www.cellsignallingbiology.org r r r Cell Signalling Biology Michael J. Berridge Module 1 Introduction 1 3 switch off this flow of information once stimuli are with- Glutamate drawn. A related OFF mechanism is receptor desensitiz- 5-Hydroxytryptamine (5-HT) (serotonin) ation, whereby receptors lose their sensitivity to external Kisspeptin stimuli. Neurotensin These cell signalling pathways utilize a variety of Noradrenaline information transfer mechanisms such as diffusion, dir- Melanocortin ect protein--proteininteractions or covalent modifications, Melatonin such as protein phosphorylation, acetylation and nitro- Tachykinins sylation. Neurokinin A The effectiveness of information transfer is greatly en- Neuropeptide K hanced through the spatial and temporal aspects of cell Substance P signalling pathways. Vasoactive intestinal polypeptide (VIP) Each cell type has a unique repertoire of cell signalling Hormones and Local Hormones components that will be referred to here as the cellular signalsome. During the final stages of development, cells Activin express a particular phenotype, and this process of dif- Adrenaline ferentiation includes the expression of a distinctive set of Adenosine signalling components (a cell-type-specific signalsome) re- Angiotensin II quired to control their particular functions. These signal- Adiponectin somes have a high degree of plasticity and are constantly Adrenocorticotropic hormone (ACTH) being remodelled to cope with changing demands. Abnor- Aldosterone mal remodelling of cellular signalsomes