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Be ready to answer! Be ready to answer! 3.D.3 Signal Transduction Signal transduction pathways link signal reception with cellular response. Many chemical messengers cannot cross the plasma membrane. Signal transduction is the process by which an extracellular signal is converted to an intracellular response. Signaling begins with the recognition of a chemical messenger, a ligand, by a receptor protein. A ligand can be: • • • • • Ions Proteins (hormones) Neurotransmitters Steroids Many other types Different receptors recognize different ligands in a specific one-to-one relationship. When a ligand binds to a receptor, it causes the receptor protein’s shape to change (conformational change). The conformational change of the receptor initiates transduction of the signal. Types of Receptors: G Protein Receptors Ligand-gated Ion Channels Receptor Tyrosine Kinases G-protein coupled receptors - Receptor in PM with 7 alpha helices - Works with another protein that binds the energy-rich GTP • G-protein on cytoplasmic side (loosely bound) acts like on/off switch – GDP bound= off – GTP bound=on • G-protein usually works with receptor and an enzyme • Ligand binds to extracellular side of receptor • Causes a conformational change on cytoplasmic side, which binds the inactive G-protein • Binding causes GTP to replace GDP • The G-protein activates • The active G-protein dissociates and diffuses along the membrane • Binds the enzyme, which alters its shape and activity • The active enzyme triggers the next step • The G-protein also acts as its own GTPase enzyme – Hydrolyzes its GTP to GDP – Inactivates the G-protein • Returns to original state for re-use G Protein-Coupled Receptors • Used in: – – – – – Yeast mating factors Epinephrine and many other hormones Neurotransmitters Embryonic development Sensory reception (vision, smell in humans) • Involved in many human diseases – – – – Cholera Whooping cough Botulism Others Types of Receptors: G Protein Receptors Ligand-gated Ion Channels Receptor Tyrosine Kinases Ligand-Gated Ion Channels (Ion Channel Receptors) - Membrane receptor has a “gate” - Ligand binds specific site on extracellular side Ligand-Gated Ion Channels (Ion Channel Receptors) - The gate opens or closes - Rapid changes in ion concentration causes a response Ligand-Gated Ion Channels (Ion Channel Receptors) - Very important in nervous system - Some are controlled by electrical signals instead of ligands (voltage-gated ion channels) Ligand-gated Ion Channels: Model: the Sodium Channel The ligand that binds to the ion-gated sodium channel is the neurotransmitter acetylcholine. The sodium channel is closed when acetylcholine is not bound to the receptor. The sodium channel opens when acetylcholine is bound the receptor site. Sodium is then able to diffuse into the cell down its concentration gradient. Types of Receptors: G Protein Receptors Ligand-gated Ion Channels Receptor Tyrosine Kinases Receptor Tyrosine Kinases - Kinase= enzyme that catalyzes the transfer of phosphate groups - Tyrosine kinase receptors= attach phosphates to tyrosines (a kind of amino acid) on a substrate protein • Prior to the ligand binding, the receptors are individual polypeptides – Alpha-helix part spans membrane – Tails inside cell with many tyrosines • Signal binds (such as a growth factor) • The two receptor polypeptides associate closely and form a dimer (dimerization) • Dimerization activates the tyrosine kinase region of each polypeptide • Each TK adds a phosphate from an ATP to a tyrosine on the tail of the other polypeptide • The receptor is fully activated as a result • Specific relay proteins recognize it • Each protein binds to a specific phosphorylated tyrosine • Binding changes the shape of each protein and activates it • Each activated protein triggers a transduction pathway • **One RTK complex can activate 10+ transduction pathways and cellular responses! • Cell growth and cell reproduction are often controlled by Receptor Tyrosine Kinases • Abnormal RTKs that function without ligands may contribute to some cancers INTRACELLULAR RECEPTORS Intracellular Receptors • Found in the cytoplasm or nucleus • Must be reached by molecules that are: – Small enough, or – Hydrophobic enough Intracellular Receptors • Molecules that can do this: – Steroid hormones (testosterone, estrogen, etc) – Thyroid hormones – Nitric oxide (NO) Hormone example • Hormone binds with receptor • Complex reaches the nucleus • Binds to specific genes • The bound protein acts as a transcription factor“calls in” the machinery to copy the gene and translate it into a protein SUMMARY Ligands interact with receptors to initiate a sequence inside the cell. An Example Signal Transduction Pathway Signaling cascades often amplify the incoming signals, with the result of appropriate responses by the cell. Second messengers are often essential to the function of the cascade. Many signal transduction pathways cause: • Protein modifications such as methylation that change the signaling process and regulate cell processes. • Phosphorylation cascades that amplify the signal.