Cell Signaling Mechanisms Learning Objectives At the end of the lecture student should be able to understand; • Significance of cell signaling •First and second messengers •Cell surface types and different forms of intracellular receptors •Four features of signal transducing system •Six general types of signal transduction •The first messengers classification •G-protein linked signal transduction •Ca+2 as an intracellular receptor •Phospholipase C system of signal transduction Cell Signaling: Responding to the outside w orld • Cells interact with their environment by interpreting extracellular signals via proteins that span their plasma membrane called receptors • Receptors are comprised of extracellular and intracellular domains • The extracellular domain relays information about the outside world to the intracellular domain Cell Signaling: responding to the outside w orld • The intracellular domain then interacts with other intracellular signaling proteins • These intracellular signaling proteins further relay the message to one or more effector proteins • Effector proteins mediate the appropriate response Cell Signaling: responding to the outside world • This event is transduced into secondary responses within the cell that can be divided into four broad categories: • (1) ion channel activation, • (2) G-protein activation, • (3) activation of enzyme activity within the cell, • (4) direct activation of transcription Some signals to which cell respond Cell surface receptors • Signaling molecules include peptide hormones, catechol-amines, insulin, growth factors, cytokines, etc • Binding, and subsequent events, triggers an or in the cytosolic concentration of a second messenger; or the activated,bound receptor acts as a scaffold to recruit and activate other intracellular proteins Intracellular Receptors • Signaling molecules include steroid hormones, retinoids,thyroxine, etc • Receptor-hormone complex acts a transcription factor to alter transcription of certain genes Receptor Characteristics • Participates in transduction of the signal from the external messenger to some component of the metabolic machinery • Has at least one additional functional site which is altered by ligand binding (allosteric site) • Extracellular ligands are called "first messengers" and the intracellular mediators are called "second messengers." Four features of signal transducing system Advantages • Each cell is programmed to respond to specific combinations of signaling molecules • Different cells can respond differently to the same chemical signal Si x general types of si gnal transducers Categories • Peptides or polypeptides - insulin, glucagon, growth hormone, insulin-like growth factors, vasopressin, prolactin…. • Glycoproteins - follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH)… • Steroids - glucocorticoids (aldosterone, cortisol), steroids (progesterone, testosterone), retinoic acid… • Amino acid derivat ives - epinephrine, norepinephrine, thyroxine, triidothyronine AGONISTS vs. ANTAGONISTS Agonist mimics a hormone in binding productively to a receptor Antagonist mimics a hormone stereochemically, but binds to the receptor non-productively, inhibiting the action of the natural hormone Agonist Hormone e.g. important therapy binds 2 receptor in heart muscle Antagonist in asthma ncreased heart rate ontrol heart beat Three largest classes of cell surface receptors Ion Channel linked receptor G protein-linked Membrane Receptors e.g. Glucagon, Epinephrine and Thrombin as signaling molecules • Activates a chain of events alterat ions in concentrat ions of signal ing molecules; elaborate sets of interact ing molecules that can relay s ignals from cel l surface to the nucleus C omponents: • R eceptor; Transducer (G protein ): • Effector (me mbrane-bound en zyme); • Second messenger (e.g. cA M P); • R esponse (casca de of hi ghly- regu lated protein phosphorylat ions, et c) R ECEPTOR: • typica lly a seven transmembrane • domain, integra l membrane Characteristics of G proteins 1. . G protein is an trimeric protein which binds guanine nucleotides 2. They function to couple integral membrane receptors to target membrane-bound enzymes 3. They can be considered molecular switches where in GDP (inactive) GTP (active) + 4. The dissociated subunit expresses GTPase activity. Enzyme linked cell surface receptor Phospholipase C mechanism Hormonal involvement in responses to a stimulus Ca+2 acting as an intracellular receptors Cells must work very hard to maintain low intracellular [Ca 2+] in order for Ca2+ to result in effective intracellular signaling. Cellular mechanisms that maintain very low intracellular Ca 2+ concentrations A: Ca2+ is actively pumped out of the cytosol. B: Ca2+ is pumped into the ER and mitochondria.