SF-19 Cell Signaling I - Lecture Notes PDF

College of Osteopathic Medicine Session Name: SF.19 Cell Signaling I Instructor: Dr. Vinoth Sittaramane Course: Scientific Foundations SFOM 7801  Session objectives 1. Compare and contrast the basic properties of endocrine, autocrine, and paracrine signaling....

College of Osteopathic Medicine Session Name: SF.19 Cell Signaling I Instructor: Dr. Vinoth Sittaramane Course: Scientific Foundations SFOM 7801  Session objectives 1. Compare and contrast the basic properties of endocrine, autocrine, and paracrine signaling. 2. Review the properties that characterize receptor signaling systems. 3. Describe the mechanics and regulation of G-Protein Coupled Receptor Signaling. 4. Discuss the mechanics and regulation of inhibitory G proteins. 5. Analyze and evaluate the role of G-Protein Coupled Receptor signaling in health and disease. Types of Intercellular Signaling Introduction of Cellular Signaling Properties of Cell Signaling Types of Receptors and Signaling Pathways  G Protein-Coupled Receptor Signaling A plasma membrane receptor with seven transmembrane helical segments, an enzyme in the plasma membrane that generates an intracellular second messenger, and a guanosine nucleotide–binding protein (G protein). G-protein cycles between active (GTP-bound) and inactive (GDP-bound) forms, an effector enzyme or ion channel in the plasma membrane that is regulated by the activated G protein. Human genome – > 800 GPCRs Allergies, Depression, Blindness, Diabetes, and Cancers Epinephrine Signaling The GTPase Switch cAMP as second messenger activates Protein Kinase A  Terminating GPCR Signaling As epinephrine concentration drops below Kd for its receptors, the hormone dissociates from the receptor and the receptor reassumes its inactive conformation. Hydrolysis of GTP bound to the Gα subunit, catalyzed the intrinsic GTPase activity of the G protein. Unable to stimulate adenyl cyclase. GTPase activator proteins (GAPs) can stimulate GTPase activity, causing more rapid inactivation of the G protein. Third mechanism is to remove the second messenger: cAMP is hydrolyzed to 5’-AMP by cyclic nucleotide phosphodiesterase enzyme. Action of Phosphoprotein phosphatases, which hydrolyze phosphorylated Ser, The, or Tyr residues, releasing inorganic phosphates. A-Kinase Anchoring Protein Receptor Desensitization by β-ARK  Inhibitory G Proteins Binding of somatostatin to its receptors in the pancreas leads to activation of an inhibitory G protein or Gi, structurally homologous to Gs. However, it inhibits adenyl cyclase and lowers cAMP concentration. Thus, somatostatin inhibits the secretion of several hormones including glucagon. Tissues with α2 adrenergic receptors – epinephrine lowers cAMP concentration by inhibitory Gi. Gq – Coupled Receptor Signaling Cellular Calcium Signaling Protein Regulation by Calmodulin  GPCRs in Vision In rod and cone cells, light activates rhodopsin, which activates the G protein transducin. The freed α subunit of transducin activates a cGMP phosphodiesterase, which lowers [cGMP] and thus closes cGMP- dependent ion channels in the outer segment of the neuron. The resulting hyperpolarization of the rod or cone cell carries the signal to the next neuron in the pathway.  GPCRs in Vision, Olfaction and Gustation In olfactory neurons, olfactory stimuli, acting through GPCRs and G proteins, trigger an increase in [cAMP] by activating adenyl cyclase or [Ca2+] by activating PLC. They affect ion channels and thus membrane potential. Gustatory neurons have GPCRs that respond to tastants by altering levels of cAMP, which changes the membrane potential by gating ion channels. Vision, olfaction, and gustation in humans employ GPCRs, which act through G proteins to change the membrane potential of a sensory neuron. GPCR Signaling in Cancer  Cholera Toxin Mechanism The bacterial toxin that causes cholera is an enzyme that catalyzes transfer of the ADP-ribose moiety of NAD+ to an Arg residue of Gs. The G proteins thus modified fail to respond to normal hormonal stimuli. The pathology of cholera results from defective regulation of adenylyl cyclase and overproduction of cAMP.  Orexin and Sleep Mechanism Narcolepsy is a disorder of the organization of the sleep–wake cycle, in which people exhibit excessive daytime sleepiness and cataplexy. Orexin neuron stimulation is required to maintain wakefulness. Orexin-receptor agonists to treat narcolepsy and orexin-receptor antagonists to treat insomnia. Orexin-receptor antagonist suvorexant for the treatment of insomnia in many countries. Epinephrine and Synthetic Analogs Epinephrine, also called adrenaline, is released from the adrenal gland and regulates energy yielding metabolism in muscle, liver, and adipose tissue. It also serves as a neurotransmitter in adrenergic neurons. Its affinity for its receptor is expressed as a dissociation constant for the receptor-ligand complex. Isoproterenol is an agonist with affinity higher than epinephrine. Used for treatment of acute bradycardia, heart block & shock. Propanolol an antagonist with extremely high affinity. Used for treatment of hypertension, angina, cardiac arrythmia, thyrotoxicosis. Textbook References and Other Resources 1.Lehninger Principles of Biochemistry, 7e: Chapter 12. 2.Becker’s World of the cell, 9e: Chapter 23. 3. Baynes. Medical Biochemistry (6ed.). https://www-clinicalkey- com.ezproxy.shsu.edu/#!/browse/book/3-s2.0-C20200021304 Practice Questions High-Yield Q & A Review for USMLE Step 1: Biochemistry and Genetics | AccessMedicine | McGraw Hill Medical (mhmedical.com)