Neurophysiology:Part II

1. Neurophysiology:Part II Lecture II

2. Let’s Review • What does an action potential “spike” look like? When is depolarization, neutralization ? Hyperpolarization? What is happening to ion channels at these times? What is happening the neuron at this time? • Compare and contrast the speed of propagation in varying axons with respect to thickness and with respect to myelination. • Axonsomatic, axonaxonatic and axondendritic: a diagram.

8. NEUROTRANSMITTERS

9. Otto Loewi’s Experiment

10. Discovery of Neurotransmitters • Histological observations revealed gap between neurons (synaptic cleft) • Otto Loewi (1873-1961) demonstrated the function of neurotransmitters • flooded exposed hearts of 2 frogs with saline • Repeatedly stimulated vagus nerve ---Slowed 1st heart slowed • removed saline from that 1st frog heart and transferred it to the second frog heart. The second frog heart decreased its beat. Loewi concluded that the nerve released a chemical --- “vagus substance” • later renamed acetylcholine

11. Nitric Oxide: The Strangest ………..Neurotransmitter?!? • Nitric oxide (NO) is a gas. It is highly reactive; that is, it participates in many chemical reactions. (It is one of the nitrogen oxides ("NO") in automobile exhaust and plays a major role in the formation of photochemical. In high concentrations this is a poisonous gas! • NO is now known to be a neurotransmitter! Huh?? Yup. So, then, what is criteria for neurotransmitter you ask?

12. Our Goal Today Is To Attempt to Answer the Following Questions: • What is a Neurotransmitter? • How are Neurotransmitters classified? • How are Neurotransmitters synthesized in the body? • Compare and contrast the effects of Neurotransmitters which are one of three : ionotropic, metabotropic or modulatory.

13. Generally Speaking…. • Neurotransmitters, along with electrical signals, are the “language of the nervous system! • More than 50 neurotransmitters have been identified but we know there are over 100 in existence. • Released by the PRESYNAPTIC neuron from vesicles, usually, one or two per neuron, but each neuron can receive many kinds. • Neurotransmitters are classified chemically and functionally.

14. Nitric oxide functions as a signaling molecule that tells the body to make blood vessels relax and widen. This physiological reaction is important when the body needs more blood--the brain signals to the blood vessels near the arms, for example, when the arms need more blood supply for muscle movement or for warmth. Thus, NO works as a signaling molecule in the cardiovascular system, the nervous system, and in other tissues. Viagra’s Secret

15. The brain sends signals to NANC cells in the artery. The NANC cells release nitric oxide (NO). Nitric oxide acts as a signaling molecule and stimulates an enzyme called guanylate cyclase in nearby cells. The guanylate cyclase converts a chemical called GTP into another chemical called cGMP. cGMP causes muscles in the walls of the arteries to relax. This relaxation increases blood flow. Meanwhile, PDE is decomposing the cGMP and turning it back into GTP. There is a cycle -- guanylate cyclase turns GTP into cGMP, and PDE turns cGMP into GTP. Nitric oxide turns the cycle on.

16. are chemicals that are used to relay, amplify and modulate electrical signals between one neuron and another . It is synthesized endogenously, that is, within the presynaptic neuron It is available in sufficient quantity in the presynaptic neuron to exert an effect on the postsynaptic neuron; Externally administered, it must mimic the endogenously-released substance; A biochemical mechanism for inactivation must be present. Neurotransmitters(Definition)

17. Types of Neurotransmitters Acetylcholine • formed from acetic acid and choline MOST NTs are classified in one of the following 3 groups: Notice that each is formed from amino acids. Amino acids • GABA • glycine • aspartic acid • glutamic acid Monoamines • synthesized by replacing –COOH in amino acids with another functional group • Catecholamines • (Epinephrine, Norepinephrine and Dopamine) • Indolamines • (serotonin and histamine) Neuropeptides • long chains of amino acids ( 2 to 40) Continued on next slide.

18. Neurotransmitter: Chemical Structures

19. Production of NTs

20. Chains of 2 to 40 amino acids Stored in axon terminal as larger secretory granules (called dense-core vesicles) Act at lower concentrations Longer lasting effects Some released from nonneural tissue gut-brain peptides cause food cravings Some function as hormones modify actions of neurotransmitters To date there are around fifty peptides, which are known to act as neuronal messengers. Substance P, gastrin,cholecystokinin (CCK) neuropeptide Y, enkephalin and endorphoin B dynorphin are just a few. Neuropeptides

21. Peptides are essentially Proteins and require a sequence of amino acids. We are basically talking about transcription and translation for synthesis. Sorting and packaging ( ER and Golgi) Neuropeptides are produced in the soma and transported to terminal where they are stored in vesicles. Neuropeptide Synthesis

22. How Do Newly Synthesis Proteins (NTs) travel to the Axon Terminal So Quickly? Micotubules and motor proteins are needed for Vesicles quickly to the axon terminal or synaptic knob. Newly synthesized membrane and secretory proteins destined for the axon travel by fast anterograde transport.

23. What is Retrograde transport? • This is transport in the opposite direction. • Used mainly to transport “empty” vesicles to soma for reloading purposes. • Again, motor proteins and microtubules work are at instrumental here.

24. Ionotropic • This means the neurotransmitter attaches to a receptor on the membrane and thereby almost immediately opens the gates for some type of ion ( i.e. SODIUM gates) • If, indeed, the NT opens sodium gates and enables Na+ to enter postsynaptic cell ..depolarizing membrane…We say that the NT is excitatory with ionotrophic effects

25. Ionotropic with Inhibitory • GABA ()a NT, attaches to the membrane receptor but this one opens a Cl- gate • Cl- ions rush in the membrane causing the membrane to hyperpolarize, rather than depolarize….NOW the neuron is less likely to form an AP. • SO GABA inhibitorywith ionotropic effects

26. Excitatory Cholinergic Synapse(Example of Excitatory NT w/ Ionotropic Effects • Nerve signal opens voltage-gated calcium channels in synaptic knob • Triggers release of ACh which crosses synapse • ACh receptors trigger opening of Na+ channels producing local potential (postsynaptic potential) • When reaches -55mV, triggers APin postsynaptic neuron

27. Synaptic Transmission 3 kinds of synapses with different modes of action • Excitatory cholinergic synapse = ACh • Inhibitory GABA-ergic synapse = GABA • Excitatory adrenergic synapse = NE Synaptic delay (.5 msec) • time from arrival of nerve signal at synapse to start of AP in postsynaptic cell

29. Inhibitory GABA-ergic Synapse • Nerve signal triggers release of GABA (-aminobutyric acid) which crosses synapse • GABA receptors trigger opening of Cl- channels producing hyperpolarization • Postsynaptic neuron now less likely to reach threshold

30. Excitatory Adrenergic Synapse • Neurotransmitter is NE (norepinephrine) • Acts through 2nd messenger systems (cAMP) • receptor is an integral membrane protein associated with a G protein, which activates adenylate cyclase, which converts ATP to cAMP • cAMP has multiple effects • binds to ion gate inside of membrane (depolarizing) • activates cytoplasmic enzymes • induces genetic transcription and production of new enzymes • Its advantage is enzymatic amplification

31. Neurotransmitter is NE (norepinephrine) Acts through 2nd messenger systems (cAMP) receptor is an integral membrane protein associated with a G protein, which activates adenylate cyclase, which converts ATP to cAMP cAMP has multiple effects binds to ion gate inside of membrane (depolarizing) activates cytoplasmic enzymes induces genetic transcription and production of new enzymes Its advantage is enzymatic amplification Excitatory Adrenergic Synapse/Metabotropic Effects

32. Neuromodulators • This is when your neurotransmitter acts like hormone and modulates activities. • NO is considered a neuromodulator as well as many of the neuropeptides

33. Postsynaptic Potentials- EPSP • Excitatory postsynaptic potentials (EPSP) • a positive voltage change causing postsynaptic cell to be more likely to fire • result from Na+ flowing into the cell • glutamate and aspartate are excitatory neurotransmitters • ACh and norepinephrine may excite or inhibit depending on cell

34. Postsynaptic Potentials- IPSP • Inhibitory postsynaptic potentials (IPSP) • a negative voltage change causing postsynaptic cell to be less likely to fire (hyperpolarize) • result of Cl- flowing into the cell or K+ leaving the cell • glycine and GABA are inhibitory neurotransmitters • ACh and norepinephrine may excite or inhibit depending upon cell

35. Chains of 2 to 40 amino acids Stored in axon terminal as larger secretory granules (called dense-core vesicles) Act at lower concentrations Longer lasting effects Some released from nonneural tissue gut-brain peptides cause food cravings Some function as hormones modify actions of neurotransmitters To date there are around fifty peptides, which are known to act as neuronal messengers. Substance P, gastrin,cholecystokinin, neuropeptide Y, enkephalin and endorphoin B dynorphin are just a few. Neuropeptides

40. It is believed that cocaine boosts dopamine release and blocks its reuptake by dopamine transporters. This leaves more dopamine saturating synaptic clefts to overstimulate critical brain sites which cause the sensation of euphoria. How Cocaine Causes Euphoria

41. Different Drugs have different “receptor sites” in the Brain for the NT. NT gives a Euphoria at the site in brain. This is often thought of as a “reward pathway”. From Synapse to Receptor Site