1. CHEMICAL COMMUNICATION HORMONES & NEUROTRANSMITTERS

2. Introduction There are three principal types of molecules used for communications –Receptors: –Receptors: proteins embedded in the surface membranes of cells –Chemical messengers: –Chemical messengers: chemicals that interact with receptors; also called ligands –Secondary messengers: –Secondary messengers: chemicals that carry a message from a receptor to the inside of a cell and amplify the message

3. A large percent of drugs used in human medicine influence chemical communication (see Table 23.1) - antagonist: - antagonist: a molecule that blocks a natural receptor and prevents its stimulation - agonist: - agonist: a molecule that competes with a natural messenger for a receptor site; it binds to the receptor site and elicits the same response as the natural messenger - a drug may decrease (by controlling its release) or increase (by inhibiting its removal from receptors) the effective concentration of messenger

4. Other terms and definitions neuron: neuron: a nerve cell neurotransmitter neurotransmitter: a compound involved in communication between neurons or between a neuron and a target tissue; it acts across a synapse hormone: hormone: a compound that is synthesized in one location, travels large distances, usually in the blood, and then acts at a remote location (see Table 23.2). The distinction between a neurotransmitter and a hormone is physiological, not chemical; it depends on whether the molecule acts over a short distance (across a synapse) or over a long distance (from the secretory organ, through the blood, to its site of action)

5. Fig. 23.1, p.573 Neuron and synapse

7. There are five classes of chemical messengers: cholinergic messengers amino acid messengers adrenergic messengers peptidergic messengers steroid messengers Messengers are also classified by how they work; they may –activate enzymes –affect the synthesis of enzymes –affect the permeability of membranes –act directly or through a secondary messenger

8. CLASSES OF CHEMICAL MESSENGERS Cholinergic - acetylcholine – neurotransmitter, transfers nerve impulse to muscle cells Amino acid – simple amino acids & modified amino acids – neurotransmitters Adrenergic - monoamines similar to epenephrine (adrenalin) - neurotransmitters & hormones Peptidergic – peptides & proteins – neurotransmitters & hormones Steroid - steroids - hormones & neurotransmitters

10. ACETYLCHOLINE

11. Acetylcholine The main cholinergic messenger is acetylcholine Cholinergic receptors –there are two kinds of receptors for acetylcholine –we look at the one that exists in motor end plates of skeletal muscles or in sympathetic ganglia

12. Acetylcholine – synthesized in presynaptic cell, stored in vesicles. Release is triggered by the buildup of Ca2+ ions. Acetylcholine moves across the synapse & forms a complex with receptor. Opens a channel for ion flow & creates a flow of charge by exchanging Na+ and K+ - this constitutes a nerve impulse. Acetylcholine is broken down & removed from the receptor by acetylcholinesterase.

13. Storage and release of acetylcholine (ACh) –the message is initiated by calcium ions, Ca 2+ –the nerve cells that bring messages contain ACh stored in vesicles –when Ca 2+ concentration becomes more that about 10 -4 M, the vesicles that contain ACh fuse with the presynaptic membrane of nerve cells and empty ACh into the synapse –ACh travels across the synapse and is absorbed on specific receptor sites

14. Chem Connect 23A, p.578

15. Action of the acetylcholine (cont’d) –the presence of ACh on the postsynaptic receptor triggers a conformation change in the receptor protein –this change opens an ion channel and allows ions to cross membranes freely –Na + ions have higher concentration outside the neuron and pass into it –K + ions have higher concentration inside the neuron and leave it –this change of Na + and K + ion concentrations is translated into a nerve signal –after a few milliseconds, the ion channel closes

16. Acetylcholine

17. Removal of ACh –ACh is removed from the receptor site by hydrolysis catalyzed by the enzyme acetylcholinesterase this rapid removal allows nerves to transmit more than 100 signals per second

18. Control of neurotransmission –acetylcholinesterase is inhibited irreversibly by the phosphonates in nerve gases and some pesticides (ChemCom 23B) –it is also inhibited by these two compounds

19. Control of transmission (cont’d) –another control is to modulate the action of the ACh receptor ligand-gated ion channels –because ACh enables ion channels to open and propagate signals, the channels themselves are called ligand-gated ion channels –the attachment of the ligand to the receptor is critical to signaling –nicotine in low doses is a stimulant; it is an agonist because it prolongs the receptor’s biochemical response –nicotine in high doses is an antagonist and blocks the action of the receptor

20. Amino Acids Amino acid messengers excitatory neurotransmitters –some amino acids are excitatory neurotransmitters; examples are Glu, Asp, and Cys inhibitory neurotransmitters –others are inhibitory neurotransmitters; examples are Gly and these three

21. Amino Acid Messengers Receptors –Glu has at least five subclasses of receptors –the best known among these is the N-methyl-D- aspartate (NMDA) receptor –this receptor is a ligand-gated ion channel –when Glu binds to the receptor, the ion channel opens, Na + and Ca 2+ ions flow in, and K + ions flow outNMDA is an agonist and also stimulates the receptor

22. Adrenergic Messengers Monoamine messengers

23. G protein hydrolyzes GTP,activating adenylate cyclase which forms cAMP cAMP activates protein kinase; ATP phosphorylates catalytic unit Catalytic unit phosphorylates ion- translocating protein, & opens ion gates.

24. Adrenergic Messengers When norepinephrine is absorbed onto the receptor site –the active G-protein hydrolyzes GTP –the energy of hydrolysis activates adenylate cyclase

25. Cyclic AMP (cAMP) –cAMP is synthesized in cells from ATP

26. Adrenergic Messengers –cyclic AMP activates protein kinase by dissociating the regulatory (R) unit from the catalytic (C) unit

27. Adrenergic Messengers –the catalytic unit phosphorylates the ion- translocating protein that blocks the channel ion flow –the phosphorylated ion-translocating protein changes its shape and position and opens the ion gate

28. Adrenergic Messengers Removal of the signal –when the neurotransmitter or hormone dissociates from the receptor, adenylate cyclase stops the synthesis of cAMP –the cAMP already produced is destroyed by the enzyme phosphodiesterase, which catalyzes the hydrolysis of one of the phosphodiester bonds to give AMP

29. Adrenergic Messengers Control of neurotransmission –the G-protein-adenylate cyclase cascade in transduction signaling is not limited to monoamine messengers –among the other neurotransmitters and peptide hormones using this signaling pathway are glucagon, vasopressin, luteinizing hormone, enkephalins, and P-protein –a number of enzymes can be phosphorylated by protein kinases and the phosphorylation controls whether these enzymes are active or inactive

30. Adrenergic Messengers Removal of neurotransmitter –the body inactivates monoamines by oxidation to an aldehyde, catalyzed by monoamine oxidases (MAOs)

31. Histamine –H 1 receptors are found in the respiratory tract where they affect the vascular, muscular, and secretory changes associated with hay fever and asthma; antihistamines that block H 1 receptors relieve these symptoms –H 2 receptors are found mainly in the stomach and affect the secretion of HCl; cimetidine and ranitidine block H 2 receptors and thus reduce acid secretion

32. The first brain peptides isolated were the enkephalins –these pentapeptides are present in certain nerve cell terminals –they bind to specific pain receptors and seem to control pain perception Neuropeptide Y, a potent orexic, affects the hypothalamus Substance P, an 11-amino acid peptide is involved in the transmission of pain signals

34. Peptidergic Messengers All peptidergic messengers, hormones, and neurotransmitters act through secondary messengers –glucagon, luteinizing hormone, antidiuretic hormone, angiotensin, enkephalin, and substance P use the G-protein-adenylate cyclase cascade.Others such as vasopressin use membrane-derived phosphatidylinositol (PI) derivatives

35. Steroid Messengers A large number of hormones are steroids –these hormones are hydrophobic and, therefore, cross plasma membranes by diffusion –steroid hormones interact inside cells with protein receptors –most of these receptors are located in the nucleus, but small numbers also exist in the cytoplasm –once inside the nucleus, the steroid-receptor complex can either bind directly to DNA or combine with a transcription factor

37. Modes of hormone action Activate enzymes ex. – epinephrine Alter gene transcription & the synthesis of enzymes ex. – steroids Alter the permeability of membranes ex. - insulin