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Biochemistry 2/e - Garrett & Grisham Chapter 34 The Reception and Transmission of Extracellular Information to accompany Biochemistry, 2/e by Reginald Garrett and Charles Grisham All rights reserved. Requests for permission to make copies of any part of the work should be mailed to: Permissions Department, Harcourt Brace & Company, 6277 Sea Harbor Drive, Orlando, Florida 32887-6777 Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Outline • 34.1 Hormones and Signal Transduction Pathways • 34.2 Signal-Transducing Receptors Transmit the Hormonal Message • 34.3 Intracellular Second Messengers • 34.4 GTP-Binding Proteins” The Hormonal Missing Link • 34.5 The 7-TMS receptor Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Outline • • • • • • • 34.6 Specific Phospholipases 34.7 Calcium as a Second Messenger 34.8 Protein Kinase C 34.9 The Single TMS-receptor 34.10 Protein Modules 34.11 Steroid Hormones SPECIAL FOCUS: Neurotransmission and Sensory Systems Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Classes of Hormones (There may be others, but we doubt it...) • Steroid Hormones - derived from cholesterolregulate metabolism, salt/water balances, inflammation, sexual function • Amino Acid Derived Hormones - epinephrine, etc.- regulate smooth muscle , blood pressure, cardiac rate, lipolysis, glycogenolysis • Peptide Hormones - regulate many processes in all tissues - including release of other hormones Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Signal-Transducing Receptors Transmit Hormone Message • Non-steroid hormones bind to plasma membrane and activate a signaltransduction pathway inside the cell • Steroid hormones may either – bind to the plasma membrane – or – enter the cell and travel to the nucleus Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Types of Receptors Three that we know of... • 7-transmembrane segment receptors – extracellular site for hormone (ligand) – intracellular site for GTP-binding protein • Single-transmembrane segment receptors – extracellular site for hormone (ligand) – intracellular catalytic domain - either a tyrosine kinase or guanylyl cyclase • Oligomeric ion channels Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Second Messengers • • • • Many and there may be more! The hormone is the "first messenger" The second messenger - Ca2+, cAMP or other - is released when the hormone binds to its (extracellular) receptor The second messenger then activates (or inhibits) processes in the cytoplasm or nucleus Degradation and/or clearance of the second messenger is also (obviously) important Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham cAMP and Glycogen Phosphorylase Earl Sutherland discovers the first second messenger • In the early 1960s, Earl Sutherland showed that the stimulation of glycogen phosphorylase by epinephrine involved cyclic adenosine-3',5'monophosphate • He called cAMP a "second messenger" • cAMP is synthesized by adenylyl cyclase and degraded by phosphodiesterase Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham How are the hormone receptor and AC coupled? • Purified AC and purified receptor, when recombined, are not coupled. • Rodbell showed that GTP is required for hormonal activation of AC • In 1977, Elliott Ross and Alfred Gilman at Univ. of Virginia discovered a GTP-binding protein which restored hormone stimulation to AC • Hormone stimulates receptor, which activates GTP-binding protein, which activates AC Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham G Proteins Many new developments in this area • Two kinds: "heterotrimeric G proteins" and "small G proteins" • X-ray diffraction structures for several of these are only recently available • Structures shed new light on possible functions Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Heterotrimeric G Proteins A model for their activity • Binding of hormone, etc., to receptor protein in the membrane triggers dissociation of GDP and binding of GTP to -subunit of G protein • G-GTP complex dissociates from G and migrates to effector sites, activating or inhibiting • But it is now clear that G also functions as a signalling device Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Signalling Roles for G() • • • • • • A partial list Potassium channel proteins Phospholipase A2 Yeast mating protein kinase Ste20 Adenylyl cyclase Phospholipase C Calcium channels • Receptor kinases Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Stimulatory and Inhibitory G G proteins may either stimulate or inhibit an effector. • In the case of adenylyl cyclase, the stimulatory G protein is known as Gs and the inhibitory G protein is known as Gi • Gi may act either by the Gi subunit binding to AC or by the Gi complex complexing all the Gi and preventing it from binding to AC • Read about the actions of cholera toxin and pertussis toxin Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham The ras Gene and p21ras • • • • An oncogene and its product a gene first found in rat sarcoma virus Normal cellular ras protein activates cellular processes when GTP is bound and is inactive when GTP has been hydrolyzed to GDP Mutant (oncogenic) forms of ras have severely impaired GTPase activity, so remain active for long periods, stimulating excessive growth and metabolic activity causing tumors to form Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham 7-TMS Receptors • • • • • Receptors that interact with G proteins Seven putative alpha-helical transmembrane segments Extracellular domain interacts with hormone Intracellular domain interacts with G proteins Adrenergic receptors are typical Note desensitization by phosphorylation, either by ARK or by protein kinase A Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Phospholipases Release Second Messengers • Inositol phospholipids yield IP3 and DAG • PLC is activated by 7-TMS receptors and G proteins • PLC is activated by receptor tyrosine kinases (via phosphorylation) • Note PI metabolic pathways and the role of lithium Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Other Lipids as Messengers • • • • Recent findings - lots more to come More recently than for PI, other phospholipids have been found to produce second messengers! PC can produce C20s, DAG and/or PA Sphingomyelin and glycosphingolipids also produce signals Ceramide (from SM) is a trigger of apoptosis - programmed cell death Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Ca2+ as a Second Messenger • • • • • Several sources of Ca2+ in cells! [Ca2+] in cells is normally very low: < 1M Calcium can enter cell from outside or from ER and calciosomes CICR - Calcium-Induced Calcium Release - is very, very similar to what happens at the foot structure in muscle cells! IP3 (made by action of phospholipase C) is the trigger See Figures 34.17-34.19 Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Calcium Oscillations! M. Berridge's model of Ca2+ signals • Ca2+ was once thought to merely rise in cells to signal and drop when the signal was over • Berridge's work demonstrates that Ca2+ levels oscillate in cells! • The purpose may be to protect cell components that are sensitive to high calcium, or perhaps to create waves of Ca2+ in the cell Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Ca2+-Binding Proteins • • • • Mediators of Ca2+effects in cells Many cellular proteins modulate Ca2+ effects 3 main types: protein kinase Cs, Ca2+modulated proteins and annexins Kretsinger characterized the structure of parvalbumin, prototype of Ca2+-modulated proteins "EF hand" proteins bind BAA helices Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Transduction of two second messenger signals • • • • PKC is activated by DAG and Ca2+ Most PKC isozymes have several domains, including ATP-binding domain, substrate-binding domain, Ca-binding domain and a phorbol esterbinding domain Phorbol esters are apparent analogues of DAG Cellular phosphatases dephosphorylate target proteins Read about okadaic acid Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Single TMS Receptors • • • • • • • Three main classes Extracellular domain to interact with hormone Single transmembrane segment Intracellular domain with enzyme activity Activity is usually tyrosine kinase or guanylyl cyclase Each of these has a "nonreceptor" counterpart src gene kinase - pp60v-src was first known Two posttranslational modifications Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Receptor Tyrosine Kinases Membrane-associated allosteric enzymes • How do single-TMS receptors transmit the signal from outside to inside?? • Oligomeric association is the key! • Extracellular ligand binding Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham The Polypeptide Hormones Common features of synthesis • All secreted polypeptide hormones are synthesized with a signal sequence (which directs them to secretory granules, then out) • Usually synthesized as inactive preprohormones ("pre-pro" implies at least two precessing steps) • Proteolytic processing produces the prohormone and the hormone Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Proteolytic Processing • • • • A mostly common pathway Proteolytic cleavage of the hydrophobic Nterminal signal peptide sequence Proteolytic cleavage at a site defined by pairs of basic amino acid residues Proteolytic cleavage at sites designated by single Arg residues Post-translational modification: C-terminal amidation, N-terminal acetylation, phosphorylation, glycosylation Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Gastrin as an Example Heptadecapeptide secreted by the antral mucosa of stomach • Gastrin stimulates acid secretion in stomach • Product of preprogastrin - 101-104 residues • Signal peptide cleavage leaves progastrin 80-83 residues • Cleavage at Lys and Arg (basic) residues and Cterminal amidation leaves gastrin • N-terminal residue of gastrin is pyroglutamate • C-terminal amidation involves destruction of Gly Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Protein-Tyrosine Phosphatases • • • • The enzymes that dephosphorylate Tyr Some PTPases are integral membrane proteins But there are also lots of soluble PTPases Cytoplasmic PTPases have N-term. catalytic domains and C-terminal regulatory domains Membrane PTPases all have cytoplasmic catalytic domain, single transmembrane segment and an extracellular recognition site Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Guanylyl Cyclases • • • • Soluble or Membrane-Bound Membrane-bound GCs are the other group of single-transmembrane-segment receptors (besides RTKs) Peptide hormones activate the membraneforms Note speract and resact, from mammalian ova Activation may involve oligomerization of receptors, as for RTKs Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Soluble Guanylyl Cyclases • • • • • Receptors for Nitric Oxide NO is a reactive, free-radical that acts either as a neurotransmitter or as a second messenger NO relaxes vascular smooth muscle (and is thus involved in stimulation of penile erection) NO also stimulates macrophages to kill tumor cells and bacteria NO binds to heme of GC, stimulating GC activity 50-fold Read about NO synthesis and also see box on Alfred Nobel Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Protein Modules in Signal Transduction • Signal transduction in cell occurs via protein-protein and protein-lipid interactions based on protein modules • Most signaling proteins consist of two or more modules • This permits assembly of functional signaling complexes Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Localization of Signaling Proteins • Adaptor proteins provide docking sites for signaling modules at the membrane • Typical case: IRS-1 (Insulin Receptor Substrate-1) – N-terminal PH domain – PTB domain – 18 potential tyrosine phosphorylation sites – PH and PTB direct IRS-1 to receptor tyrosine kinase - signaling events follow! Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Signaling Pathways from Membrane to the Nucleus • The complete path from membrane to nucleus is understood for a few cases • See Figure 34.38 • Signaling pathways are redundant • Signaling pathways converge and diverge • This is possible with several signaling modules on a signaling protein Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Module Interactions Rule! • The interplay of multiple modules on many signaling proteins permits a dazzling array of signaling interactions • See Figure 34.40 • We can barely conceive of the probable extent of this complexity • For example, it is estimated that there are more than 1000 protein kinases in the typical animal cell - all signals! Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Steroid Hormones • • • • Glucocorticoids, mineralocorticoids, vitamin D and the sex hormones May either act at nucleus or at plasma membrane Steroids are hydrophobic and cannot diffuse freely to nucleus Receptor proteins carry steroids to the nucleus Steroid receptor proteins are all apparently members of a gene superfamily and have evolved from a common ancestral precursor Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Steroid Receptor Proteins • Hydrophobic domain near C-terminus that interacts with steroid itself • Central, hydrophilic domain that binds to DNA • Central DNA-binding domains are homologous to one another, with 9 conserved Cys residues • Three pairs of Cys residues are in Cys-X-X-Cys sequences - as in Zinc-finger domains • Steroid-receptor complex may bind to DNA or to transcription factors • Thyroid hormone receptor proteins are similar Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Extracellular Effects of steroid hormones • Two lines of evidence: action of steroids on calcium channels and other membrane proteins and the speed of certain steroid hormone effects • Example: testosterone rapidly stimulates transport of glucose, calcium and amino acids into rat kidney cells • Several demonstrations now of tight binding of steroid probes to GABA receptor and other proteins Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Cells of Nervous Systems • • • • Neurons and Neuroglia (Glial Cells) Neurons contain processes, including an axon and dendrites Axon is covered with myelin sheath and cellular sheath, except at nodes of Ranvier The axon ends in synaptic termini, aka synaptic knobs or synaptic bulbs Three kinds of neurons: sensory neurons, motor neurons and interneurons Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Ion Gradients • • • • The source of electrical potentials in neurons Nerve impulses consist of electrical signals that are transient changes in the electrical potential differences (voltages) across neuron membrane Know resting concentrations Learn to use the equation for actual potential difference in the box on page S-43 Difference between Nernst potential and actual potential represents a thermodynamic push Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham The Action Potential A somewhat misleading name - it refers to the series of changes in potential that constitute a nerve impulse • Small depolarization (from -60 to -40 mV) opens voltage-gated ion channels - Na flows in • Potential rises to +30 mV, Na channels close, K channels open. K streams out, lowering potential • Action potentials flow along the axon to the synapse • Number and frequency important, not intensity Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Voltage-Gated Na, K Channels • • • • Clustered in Nodes of Ranvier See Figure 34.52 for Na, K channel effectors Arrangement of Na channel in membrane is like DHP receptor in muscle See Figure 34.55 for diagram of how the channel is formed in membrane These channels are voltage-sensitive - voltage changes cause conformational changes and gating Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Communication at the Synapse • • • • A crucial feature of neurotransmission Ratio of synapses to neurons in human forebrain is 40,000 to 1! Chemical synapses are different from electrical Neurotransmitters facilitate cell-cell communication at the synapse Note families of neurotransmitters in Table 34.6 Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham The Cholinergic Synapse • • • • A model for many others Synaptic vesicles in synaptic knobs contain acetylcholine (10,000 molecules per vesicle) Arriving action potential depolarizes membrane, opening Ca channels and causing vesicles to fuse with plasma membrane Acetylcholine spills into cleft, migrates to adjacent cells and binds to receptors Toxin effects: botulism toxin inhibits Ac-choline release, black widow's latrotoxin protein overstimulates Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Two Classes of Ac-Ch Receptor • • • • • Nicotinic and muscarinic As always, toxic agents have helped to identify and purify hard-to-find biomolecules Nicotinic Ac-Ch receptors are voltage-gated ion channels Muscarinic Ac-Ch receptors are transmembrane proteins that interact with G proteins Acetylcholinesterase degrades Ac-Ch in cleft Transport proteins and V-type H+-ATPases return Ac-Ch to vesicles - called reuptake Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Other Neurotransmitters • • • • • Excitatory and inhibitory Glutamate is good example: nerve impulse triggers Ca-dependent exocytosis of glutamate Glutamate is either returned to neuron, or carried into glial cells, converted to Gln and taken back to the neuron from which it was released See 4 types of glutamate receptors in Fig. 34.68 NMDA receptor is best understood for now Note phencyclidine (angel dust) story Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham GABA and Glycine • • • • • Inhibitory Neurotransmitters Inhibitory neurotransmitters diminish the actions of activating neurotransmitters See Figure 34.70 for glutamate degradation Excitatory glutamate is broken down to inhibitory GABA, which is broken down to non-signals GABA & glycine receptors are chloride channels Glycine receptor is site of action of strychnine Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Catecholamine Neurotransmitters • Epinephrine, norepinephrine, dopamine and L-dopa are all neurotransmitters • Synthesized from tyrosine - see Fig. 34.72 • Excessive production of dopamine (DA) or hypersensitivity of DA receptors produces psychotic symptoms and schizophrenia • Lowered production and/or loss of DA neurons are factors in Parkinsonism Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Neurological Disorders • • • • • • • Depression, Parkinsonism, etc. Defects in catecholamine processing are responsible for many neurological disorders Norepinephrine and dopamine systems are keys Breakdown of NE and DA by catechol-O-methyl transferase and monoamine oxidase Reuptake by specific transport proteins MAO inhibitors are antidepressants Tricyclics - antidepressants that block reuptake Cocaine blocks reuptake, prolongs effects of DA Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Peptide Neurotransmitters • • • • • • Lots more to learn here! Likely to be many peptide NTs Concentrations are low; purification is hard Roles are complex Endorphins and enkephalins are natural opioids Endothelins affect smooth muscle contraction, vasoconstriction, mitogenesis, tissue changes Vasoactive intestinal peptide stimulates AC (to make cAMP) via G proteins, and its effects are synergistic with those of other neurotransmitters Copyright © 1999 by Harcourt Brace & Company Biochemistry 2/e - Garrett & Grisham Sensory Transduction • Similarities between sight, taste, smell • Specialized sensory cells translate stimulus into electrical signals in adjacent neurons • Vision is the paradigm system • Absorption of light quanta by rhodopsin isomerizes retinal (11-cis to all-trans) • Light is absorbed by rhodopsin in the outer segments of rod and cone cells Copyright © 1999 by Harcourt Brace & Company