Biochemistry

1. Biochemistry Chapter 24 Chemical Communications: Neurotransmitters and Hormones

2. Problem Sets • PS #1 • Sec 24.1 – 24.4 • 3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15 • PS #2 • Sec 24.5 – 24.7 • 18, 19, 23, 24, 25, 26, 28, 29, 30, 33, 35

3. 24.1 Chemical Communications • Each cell is an isolated entity • Need to communicate with other cells in order to coordinate activity • Also needs to communicate internally – organelles need to coordinate activity • Communicate by exchanging molecules • 3 types of molecules: Receptors, chemical messengers, secondary messengers

4. 24.1 Communication Molecules • Receptors • Proteins on the surface of cells embedded in the cell membrane • Chemical Messengers (ligands) • Interact with receptors • Fit into receptor sites like lock-and-key • Secondary Messengers • Carry the message from receptor to inside cell • Amplify the message

5. 24.1 Some Terminology • Neuron – a nerve cell • Neurotransmitters – compounds that carry messages from one neuron to another or from one neuron to some other cell • Example – acetylcholine • Hormones – communication molecules secreted by endocrine glands • Example – adrenaline

6. 24.1 Ways Drugs Affect Communication • Antagonist – a drug that blocks the receptor and prevents its stimulation • Agonist – a drug that competes with the messenger for the receptor site, stimulating the receptor • Some drugs decrease concentration of the messengers by controlling their release • Others increase concentration of the messengers by inhibiting their removal

7. 24.2 Neurotransmitters • Axon: long fiber part of cell • Dendrite: hair-like receptors • Synapse: fluid-filled space between neurons • Presynaptic: side from which the neurotransmitters originate • Postsynaptic: side with receptors for neurotransmitters • Vessicles: presynaptic storage sites for neurotransmitters

8. 24.2 Hormones • Diverse compounds secreted by endocrine glands, released into bloodstream, and adsorbed onto distant receptor sites • Difference between neurotransmitters and hormones is distance • Neurotransmitters work on a short distance across a synapse (2 x 10-6 cm) • Hormones act over a large distance through the bloodstream • Some compounds can be both!

9. 24.2 Classification • Classified by chemical structure • Cholinergic, amino acid, adrenergic, peptidergic, steroid • Classified by how they work • Activate enzymes, affect synthesis of enzymes by working on gene transcription, affect membrane permeability • Classified how directly they act • Some act directly, others require a secondary messenger

11. 24.3 Cholinergic Neurotransmitters • Acetylcholine O CH3 || + |CH3 – C – O – CH2 – CH2 – N – CH3 | CH3 • Often abbreviated ACh

12. 24.3 Cholinergic Receptors • Two types – Nicotinic and Muscarinic • Nicotinic Receptors • Often found at myoneural junctions • Respond to nicotine • 5 unit transmembrane protein, ion channel • Muscarinic Receptors • Parasympathetic nervous system • Respond to muscarine • Use secondary messengers to open ion channels

13. 24.3 Action of Acetylcholine ACh attaches, triggering a conformational change that opens the ion channel Inside cell, [K+] > [Na+] More Na+ enters than K+ leaving, so cell builds up a + charge

14. 24.3 Removal of ACh ACh must be removed from receptor Acetylcholinesterase (AChE) hydrolyzes ACh Operates rapidly enough to allow transmission of more than 100 nerve signals per second

15. 24.3 Inhibition of AChE Nerve agents and pesticides irreversibly bind to AChE by phosphonylation of a serine near the active site Succinylcholine and decamethonium bromide resemble ACh and fit into the active site of AChE (competitive inhibitors)

16. 24.3 Other Means of Controlling ACh Neurotransmission • Modulation of the ion channel • Eg, nicotine prolongs the channel’s response • Acts as an agonist in low doses • In high doses it becomes an antagonist because it blocks the action of the receptor • Neurotoxins like cobra venom and curare work in the same way • Control the supply of ACh • Botulism prevents release of ACh from vessicles • Alzheimer’s impairs the synthesis of ACh

17. 24.4 Amino Acid Neurotransmitters • Some amino acids are neurotransmitters • Includes aa’s not among the 20 found in proteins • Includes other than a amino acids • Excitory neurotransmitters • Excite the receptors • Eg: glutamic acid, aspartic acid, cysteine • Inhibitory neurotransmitters • Reduce neurotransmission • Eg: glycine, b-alanine, taurine, GABA

18. 24.4 Amino Acid Receptors • Each aa has its own set of receptors • Work similar to ACh receptors • Removal of messengers • aa’s not broken down by enzymes like ACh • Transporter molecule – grabs aa and moves it back to the presynaptic side of the synapse • Process is called reuptake

19. 24.5 Adrenergic Messengers • Monoamines • Epinephrine, serotonin, dopamine, histamine • Action of monoamine messengers • Messenger adsorbed onto receptor site • Signal transduction – a cascade of events where the receptor signal is carried inside the cell and amplified into many signals • E.g., norepinephrine receptors have an associated G-protein and guanosine triphosphate (GTP) that create a signal cascade when activated

20. Norepinephrine attaches to receptor G protein hydrolyzes GTP; energy activates enzyme that produces cAMP Protein kinase has 2 subunits: R = regulatory C = catalytic cAMP dissociates R subunit from C, which activates the enzyme C subunit phosphorylates the protein that is blocking the ion channel Phosphorylated protein changes shape, opening the ion channel

21. 24.5 Secondary Messengers • Norepinephrine receptor produces a secondary messenger inside cell • Cyclic AMP (cAMP) • Manufactured from ATP • Accomplishes two goals • Converts an event outside cell to a change inside the cell, so primary messenger does not have to cross the cell membrane • Amplifies the signal; one molecule on receptor site triggers the production of many cAMP molecules

22. 24.5 Control of Neurotransmission • Secondary messengers are slow • Takes from 0.1 s to 1 min to activate • If speed is important, use acetylcholine • No secondary messengers, so it activates in a time scale of milliseconds • Removal of the signal • When the neurotransmitter dissociates from the receptor, cell halts production of cAMP • Existing cAMP is hydrolyzed by an enzyme to AMP

23. 24.5 Removal of Neurotransmitters • Most adrenergic neurotransmitters are inactivated by oxidation to aldehydes • Done by enzymes called monoamine oxidases (MAOs) • Many antidepressant drugs are MAO inhibitors • Prevent the oxidation of monoamines, so their concentration increases in the synapses • Some adrenergic messengers are carried back to the presynaptic vessicles

24. 24.5 Histamines Found in the brains of mammals Synthesized from histidine by decarboxylation Two types of histamine receptors H1 H2 Found in the respiratory tract Affect HCl secretion in the stomach Blocked by dimenhydrinate (Dramamine) anddiphenhydramine (Benadryl) Blocked by cimetidine and ranitidine (ulcer drugs)

25. 24.6 Peptidergic Messengers • Important metabolic hormones • E.g., insulin, glucagons, vasopressin, oxytocin • Enkephalins • First brain peptides identified • Pentapeptides • Bind to pain receptors (control pain perception) • Bind to same receptor sites as morphine

26. 24.6 Peptidergic Messengers • Neuropeptide Y • Affects the hypothalmus • Acts as a potent orexic (appetite stimulant) • Anorexic agents block neuropeptide Y receptors • Substance P • 11 amino-acid peptide • Involved in transmission of pain signals • With injury or inflammation, peripheral nervous system releases substance P, which binds to receptors on the spinal cord

27. 24.6 Secondary Messengers • All peptidergic messengers act through secondary messengers • Many use the G-protein adenylate cyclase cascade • Others use membrane-derived phosphatidylinositol (PI) derivatives • Activation occurs by phosphorylation • Still others use calcium ions as secondary messengers

28. 24.7 Steroid Hormones • Steroids are hydrophobic • Can diffuse across cell membrane • No need for receptors on the cell membrane • Bind with protein receptors in the nucleus • Steroid-receptor complex binds to DNA • Influence synthesis of specific proteins • Slow process – takes hours to occur • Can sometimes act on cell membrane • Influence ion gate channels • Much faster response – takes seconds