Cell signaling and receptors 10-10-23.docx

Cellular communication Signals are generally transmitted across environment in form of soluble molecules. Biggest barrier in this process is cell membrane. Signals are constantly produced and continuously received, and response must be generated. How can signals be relayed to cells? Different...

Cellular communication Signals are generally transmitted across environment in form of soluble molecules. Biggest barrier in this process is cell membrane. Signals are constantly produced and continuously received, and response must be generated. How can signals be relayed to cells? Different modes for a cell to receive stimuli include: Autocrine cells: from a cell to its own receptors (self-signalling)- observable in cancer cells. Paracrine signals: to target cells nearby by secreting soluble molecules which are able to diffuse in. Endocrine signals: target cells that are further away and travels through blood stream to target cells e.g., hormones and cytokines. Neuronal/Synaptic: deliver messages over long distances however message not broadcasted widely instead delivered quickly and specifically to individual target cells. Contact dependent: receptor and signal molecules generally on the surface (transmembrane proteins) and both need to be in close contact for signal to pass. Membrane is impermeable to large soluble molecules, so some are transported across, and others are detected outside, and a signal is transmitted into the cell- role of receptors. Receptors and ligands Ligand binds to receptors. Receptors are integral transmembrane protein. Different ligands can produce different responses at the same receptor. Some receptors have one ligand whilst others have many and vice versa. Has extracellular region that detects ligands. Has intracellular region which interacts with effectors. Receptors can be either on cell surface or intracellular. 2 types of extracellular signal molecules: Signals that consist of molecules that are too large and hydrophilic to cross the plasma membrane of target cell therefore rely on receptors on the surface of target cells to relay their message across Signals that consist of molecules that are small enough or hydrophobic enough to pass through plasma membrane and into cytosol where they bind to intracellular receptor proteins. Examples of ligands Dissolved gases Amino acids Fatty acids What is signal transduction? The process whereby one type of signal is converted to another. Receptor protein changes Activates intracellular molecules which are 2nd messengers. Receptors contains at least one binding site for ligand. A ligand induces a positive, physiological response is called an agonist. A ligand that represses a physiological response is called antagonist. Receptors can communicate the binding of a ligand to the cell. Process of cell signalling- cellular response Ligand binds to receptor which activates the receptor and recruits and activate intracellular mediators. Intracellular mediators transmit signal to effector enzymes which bring changes and are affected by production of secondary messenger. Secondary messengers alter metabolism or affect effector enzymes that activate target proteins that alter gene transcription. Types of receptors. Ligand gated ion channels- when ligand binds, initiates cell signalling. G protein coupled receptors- activates membrane bound trimeric G proteins Receptor tyrosine kinases- involved in phosphorylation and can activate cell signalling. Intracellular receptors Receptor Tyrosine Kinases (RTK) Group of transmembrane receptors. Has extracellular part where ligand binds. Sit in the membrane as monomers but when the ligand binds, it brings it together and forms a dimer which initiates their activation. Contains transmembrane domain and intracellular kinase domain. Kinases are enzymes that phosphorylates proteins therefore adds phosphate groups to specific amino acids with a OH group using ATP. 3 amino acids that can be (because they contain OH group as that’s required for phosphorylation) Serine Threonine Tyrosine Phosphorylation is one of the processes by which a protein is either activated or deactivated. Phosphorylation can be reversed by Phosphatases. RTK tyrosine kinase phosphorylate tyrosine residues. Ligand binding site formed from both molecules of dimer therefore 2 intracellular domains come together, and this activates the receptor. The intracellular kinase domains are inactive when in monomeric forms but as soon as the domains are brought together by ligand, it activates the domains, and the kinase domains phosphorylates one another (auto phosphorylation). Anything now removed or added to the protein will causes a confirmational change hence when the phosphate group is added (phosphorylation) to the receptor, it changes confirmational, therefore it becomes a binding site for downstream mediators so other molecules can recognise the phosphorylated sites and bind to receptors, so the signal transduces downstream. Another way except the phosphorylation is when RTKs uses monomeric GTPases as molecular switches. When GTPase is inactive, it is bound to GDP. When signal comes in, GDP is taken away and replaced by GTP which activates GTPase and relay signal further. GTP can then hydrolyse back to GDP and become inactive. Accessory proteins are needed for this cycle to take place. For GDP to be removed from GTPase and replaced by GTP, an activator is needed which is Guanine nucleotide exchange factor (GEF) When GTP is hydrolysed back to GDP, it is with the help of GTPase activating protein (GAP)- this then inactivates the monomeric G proteins. Consequences of phosphorylation and GTP binding Both act as molecular switches Both need to be turned off. Phosphorylation needs to be reversed by phosphatases. GTPases can hydrolyse GTP to GDP but GTPase activating proteins enhances this activity. The basic principles of how a signal is from outside of cell is relayed and conveyed inside the cell in MAPK pathway: The ligand with the signal binds to the 2 receptor monomers sitting in the membrane, it brings the 2 monomers together and forms dimer and becomes activated and phosphorylate each other. By being phosphorylated, it creates sites where other proteins such as adapter proteins can bind and become activated. The inactive protein/ GTPase which is anchored in plasma membrane has GDP bound to it. The activating protein replaces GDP and GTP and activates the protein. It further transmits the signal forward and activate different kinases which are then phosphorylated downstream proteins. Different target proteins such as enzymes and transcription factors, are also then phosphorylated. What is signal termination? Prolonged stimulation can cause damage to cells, change cell properties or cause cell death The receptor protein and the signal molecules can be encapsulated into a endosome to prevent further stimulation – receptor sequestration. Receptor and ligand complex can be drawn down to lysosomes where it is broken down and released- receptor down regulation. By removal of phosphates inhibits and inactivates it- receptor inactivation. Inhibitors can bind to downstream signalling molecule to inactivate them- inactivation of signalling proteins. Can produce inhibitory proteins, this inhibitory product can inhibit the signals- production of inhibitory proteins. Signal transduction pathways MAP kinase pathway uses both type of switches. Phosphorylation Small monomeric G proteins Signal transduction. Some receptors bind more than one ligand. Some ligands can bind to more than one receptor. Each cell responds to limited set of extracellular signals. The signal molecule alone isn’t the message, it depends on how the target cell receives and interprets the signal. Each cell is programmed to respond to specific combination of extracellular signal molecules. Different signalling molecules play a different role. 100’s of signal molecules lead to almost unlimited combinations