Cell Signaling II Lecture Notes PDF

Cell signaling II Learning objectives: ECB6 Chapter 16: 565-566; 569-573;577-583; 599-5 Understand that cell surface receptors include ion-channel-coupled receptors, G-protein- coupled receptors and enzyme-coupled receptors Understand that G-protein- coupled receptors (GPCRs) funct...

Cell signaling II Learning objectives: ECB6 Chapter 16: 565-566; 569-573;577-583; 599-5 Understand that cell surface receptors include ion-channel-coupled receptors, G-protein- coupled receptors and enzyme-coupled receptors Understand that G-protein- coupled receptors (GPCRs) function by activating the trimeric G proteins Understand how phospholipase C (PLC) is activated by GPCRs and how PLC functions in mediating signal transduction G protein-coupled Understand the concept receptor and examples of second messengers (such as IP3, DAG, Ca2+) in signal Login now to https://pollev.com/biomg1350fall22 Cell surface receptors relay extracellular signals via intracellular signaling pathways Two major types of receptors: -intracellular (steroid hormones) adaptors -cell surface Intracellular Signaling Molecules Effectors Response Figure 16-9 Essential Cell Biology 5e  Today’s topics Three main classes of cell-surface receptors Ion- G-protein Enzyme- channel- coupled coupled coupled receptors receptors receptors  Ion-channel-coupled receptors Causing a change of the permeability of the plasma membrane to specific ions, thus a change of membrane potential Very rapid responses (within milliseconds) Especially important in nerve cells and Figure 16-17b Essential Cell Biology 4e  Today’s topics Three main classes of cell-surface receptors Ion- G-protein Enzyme- channel- coupled coupled coupled receptors receptors receptors G-Protein Coupled Receptor Pathways At A Glance GPCR >700 GPCRs in human cells and their signals can be Hormones, local mediators, neurotransmitters G PROTEIN ~20 different Proteins,Gasmall proteins peptides, aa, fatty acids, each is activated by a specific set of light etc receptors each activates a particular set of downstream targets TARGETS Most frequent targets are two enzymes: Adenylyl cyclase -> cAMP Phospholipase C -> Ca2+/DAG Many possible responses: RESPONSES Secretion, contraction, heart rate glycogen or fat breakdown Smell, taste, vision etc targeting signaling pathwaysrdto treat disease ~1/3 of drugs in use today work through GPCRs Pharmaceutical revenue totaled $450 billion in the US in 2016  G protein-coupled receptors (GPCRs) st numerous class of receptors (>700 in humans) be activated by a wide variety of signaling molecules Figure 16-17b Essential Cell Biology 4e  All GPCRs have a similar structure ligand GPCRs are seven- pass transmembrane proteins Figure 16-17b Essential Cell Biology 4e  GPCRs activate G lipid tails These Gproteins proteins have three a b subunits (trimeric): a, b, g g They are different from the monomeric small G proteins (Ras, Ran, Rab, etc) They are tethered to the plasma membrane Signal binding causes a conformational change in the receptor that is transmitted to its cytoplasmic domain Activated receptor acts as a GEF for its G-protein Activated Ga and Gbg can each activate different effector proteins Once activated, a GPCR can activate many molecules of G protein Figure 16-19 Essential Cell Biology 4e G-protein a subunit switches itself off Normally, the a subunit a hydrolyzes its bound GTP to GDP within seconds This can also be aided by “GAP-like” proteins in the cell GAP=GTPase activating protein Figure 16-20 Essential Cell Biology 4e  GPCRs and G Protein activation is Inactive a b g transient receptor protein Once activated, a GPCR can activate many molecules of G protein A GPCR is deactivated when the signal is no longer available Even if signal remains bound to receptor a GPCR is eventually deactivated and recycled GPCRs and G proteins have ON&OFF state Activated a subunit Activated Mutations in signaling pathway bg subunit a subunit proteins -> constant ‘ON’ states hydrolyzes produce ‘constitutively active’ GTP->GDP mutants (e.g: an a-subunit that h thecannot hydrolyze next movie GTP) on G-protein coupled receptors! Inactive Figure 16-19 Essential Cell Biology 4e a subunit w do G proteins work to transduce the signal downstr Many G proteins activate membrane- bound enzymes that produce small messenger molecules Two major targets of GPCRs phospholipase C (PLC) produces certain lipids adenylyl cyclase generates cAMP activates PKA (Protein Kinase cellular responses  Some cell responses mediated by cyclic AMP Extracellular Signal Target tissue Major response Molecule* increase in heart rate and force Epinephrine heart of contraction Epinephrine skeletal muscle glycogen breakdown Epinephrine, glucagon fat fat breakdown Adrenocorticotropic adrenal gland cortisol secretion hormone (ACTH) *Although all of the signal molecules listed here are hormones, some responses to local mediators and to neurotransmitters are also mediated by cyclic AMP. Table 16-3 ECB5 Many G proteins activate membrane- bound enzymes that produce small messenger molecules Two major targets of GPCRs phospholipase C (PLC) produces certain lipids adenylyl cyclase generates cAMP activates PKA (Protein Kina cellular responses  Phospholipase C leads to the production of two small messenger molecules DAG Figure 16-27 Essential Cell Biology 4e  IP3 can lead to the release of Ca2+ from the ER, thus increasing the cytosolic Ca2+ level Ca2+ acts as a second messenger to trigger many biological processes! Figure 16-27 Essential Cell Biology 4e Fertilization of an egg by a sperm triggers an increase in cytosolic calcium level in the egg Sperm-egg contact activates a PLC in the egg Calcium wave in sea urchin Increased Ca2+ fertilization leads to: Physical changes of the egg shell to prevent more than one sperm from entering the egg Activation of the egg so that  IP3 can lead to the release of Ca2+ from the ER, thus increasing the cytosolic Ca2+ level DAG Figure 16-27 Essential Cell Biology 4e  DAG, in combination with Ca2+, can activate protein kinase C (PKC) DAG PKC = Protein Kinase C During fertilization, PKC activation leads to new protein synthesis Figure 16-27 Essential Cell Biology 4e  Today’s topics Three main classes of cell-surface receptors Ion- G-protein Enzyme- channel- coupled coupled coupled receptors receptors receptors  Enzyme-coupled receptors Receptors acting as Receptors associate enzymes with enzymes Figure 16-17c Essential Cell Biology 4e  Receptor tyrosine kinases (RTKs) RTKs represent one of the largest class of enzyme-coupled receptors They are activated by growth factors (signals), such as FGF (fibroblast growth factor), EGF (epidermal growth factor), etc Their cytoplasmic domains function as tyrosine protein kinases Figure 16-32 Essential Cell Biology 4e  Most RTKs activate the small GTPase Ras GEF=guanine nucleotide exchange factor ~30% of human cancers have activating mutations in Ras Figure 16-33 Essential Cell Biology 4e Ras stimulates cell proliferation via the MAP kinase pathway Ras stimulates MAPKKK the MAPKKK- > MAPK (mitogen- MAPKK -> activated protein kinase) MAPKK and pathway, thus cell proliferation MAPK Some other cancer mutations affect proteins that function in the same pathway as Ras Figure 16-34 Essential Cell Biology 4e Signaling pathways can be highly interconnected Three main classes of cell-surface receptors Ion- G-protein Enzyme- channel- coupled coupled coupled receptors receptors receptors  Signaling pathways can be highly interconnected Figure 16-40 Essential Cell Biology 4e  Different signal Aberrant signaling (always combinations ‘ON’) leads to pathological lead to different cellular conditions (e.g. cancer) outcomes Uncontrolled Tissue Growth Aberrant Differentiatio n Cell destined to die survives Invasion MIGRATE Metastasis H I  Lecture 20 Pattern Formation in Drosophila Embryo