Biochemistry Chapter 24 Chemical Communications Neurotransmitters and Hormones

Biochemistry Chapter 24 Chemical Communications: Neurotransmitters and Hormones

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

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

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

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

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

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

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!

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

24. 3 Cholinergic Neurotransmitters • Acetylcholine O CH 3 || +| CH 3 – C – O – CH 2 – N – CH 3 | CH 3 • Often abbreviated ACh

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

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

24. 3 Removal of ACh must be removed from receptor Acetylcholinesterase (ACh. E) hydrolyzes ACh Operates rapidly enough to allow transmission of more than 100 nerve signals per second

24. 3 Inhibition of ACh. E Nerve agents and pesticides irreversibly bind to ACh. E by phosphonylation of a serine near the active site Succinylcholine and decamethonium bromide resemble ACh and fit into the active site of ACh. E (competitive inhibitors)

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

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

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

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

Norepinephrine attaches to receptor G protein hydrolyzes GTP; energy activates enzyme that produces c. AMP Protein kinase has 2 subunits: R = regulatory C = catalytic c. AMP 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

24. 5 Secondary Messengers • Norepinephrine receptor produces a secondary messenger inside cell • Cyclic AMP (c. AMP) • 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 c. AMP molecules

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 c. AMP • Existing c. AMP is hydrolyzed by an enzyme to AMP

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. 5 Histamines Found in the brains of mammals Synthesized from histidine by decarboxylation Two types of histamine receptors H 1 H 2 Found in the respiratory tract Blocked by dimenhydrinate (Dramamine) and diphenhydramine (Benadryl) Affect HCl secretion in the stomach Blocked by cimetidine and ranitidine (ulcer drugs)

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

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

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

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