Ionotropic and Metabotropic Receptors

1. Ionotropic and Metabotropic Receptors

2. Recall the 2 Kinds of Synapses? Electrical • 2 neurons linked together by gap junctions • Function in nervous system: - rapid communication - bidirectional communication - excitation/inhibition at the same synapse • Some between neurons and glia cells Chemical • Signal transduction • Excitatory • Inhibitory • Slower communication • Unidirectional communication

3. Recall where chemical synapses are found?

4. Recall the Chemical Synapse?

5. Communication Across a Synapse Action Potential Voltage-gated Ca channels open Ca triggers exocytosis Nt diffuses and binds to receptor Response in cell Response is terminated by removing nt from synaptic cleft 6. Degradation Reuptake Diffusion

6. Signal Transduction at Synapses • Rate of the response is due to the mechanism by which the signal is received and transferred at the plasma membrane. • Fast responses at ionotropic receptors (channel-linked). • Slow responses at metabotropic receptors (G-protein-linked).

7. Ionotropic Receptors • The receptor is a ligand-gated ion channel. • Ligand binding directly opens ion channel. • Fast action, short latency between nt binding and response. • Response is brief.

8. Ionotropic Receptors • 5 subunits form the pore through the membrane. • Binding of ligand opens the pore. • Ions flow into or out of the cell. • Produces EPSP or IPSP (depending on the ion channel). • Rapid desensitization (loss of activity) if continuously exposed to nt. • Limits postsynaptic responding when presynaptic neurons are highly active for a period of time.

9. Ionotropic ReceptorsSensitization High Ion Flow Low Time, ms, in exposure to neurotransmitter

11. Ionotropic Receptors • Can have multiple binding sites for various neuromodulators. • Can enhance or inhibit binding of endogenous ligands. • Are good targets for drugs.

12. Fast Responses at Ionotropic Receptors

13. Metabotropic Receptors • Most common type of receptor. • Coupled to G protein. • No direct control of ion channels. • Second messengers.

14. Metabotropic Receptors • Single subunit with 7 transmembrane spanning domains. • Highly conserved across the “receptor superfamily”. • Ligand binds in cleft on external face. • Ligand binding activates G protein • G protein activate various effectors. • Sometimes the effectors are the ion channels.

15. N TM3 TM2 TM4 Asp - TM1 TM5 TM7 TM6 AC AC γ β ATP αs αs GDP GTP cAMP GDP cAMP cAMP cAMP 2) Binding of NE causes the third intracellular loop (i3) of the receptor to change conformation and bind to the GDP-bound αs subunit of the Gs protein. (Click to see animation; click again for next step) 3) Binding of i3 to the αs subunit of the Gs protein results in a conformation change in αs, causing GDP to dissociate and GTP to bind. (Click to see animation; click again for next step) 4) The GTP-bound αs subunit dissociates from the β subunit and from the βAR receptor and binds to adenyl cyclase (AC). (Meanwhile, norepinephrine may dissociate from the receptor, but the αs subunit can remain active for many seconds after this dissociation.) (Click to see animation; click again for next step) 1) The ß-adrenergic receptor is a 7-transmembrane spanning protein. A negatively charged Asp residue on the 3rd transmembrane region (TM3), along with other charged, polar residues, allows a positively charged norepinephrine (NE) molecule to bind to the hydrophobic core of the receptor. (Click to see animation; click again for next step) 6) After hydrolysis of GTP to GDP, the αssubunit returns to its original conformation, dissociates from AC (which then becomes inactive), and reforms the trimeric Gs protein complex. (Click to see animation; click again for next slide) 5) Activated adenyl cyclase produces many molecules of cAMP from ATP. (Click to see animation; click again for next step) β-adrenergic receptor N Extracellular space TM3 TM2 TM4 Asp - TM1 NE + TM5 TM7 TM6 γ β αs C i3 loop GTP GDP Gs protein Cytoplasm

16. Slow Responses at Metabotropic Receptors: Direct G-Protein Coupling

17. Slow Responses at Metabotropic Receptors: Second Messenger Coupling

18. Postsynaptic Potential • Change in membrane potential in response to neurotransmitter binding to receptor. • Can be excitatory or inhibitory: - Excitatory: likely to elicit action potential: Deporalization -Inhibitory: less likely to elicit action potential: Hypoerpolarization Membrane Stabilization

19. Excitatory Synapses • Depolarize postsynaptic cell -Brings membrane potential closer to Threshold by opening or closing ion channels. • Channels affected are: - Open Na channels - Close K channels - Open channels that are equally permeable to Na and K Causes depolarization because of the stronger force of Na to flow into the cell • Depolarization = EPSP (excitatory postsynaptic potential)

20. Fast EPSPs

21. Slow EPSPs

22. EPSPs are Graded Potentials • Higher freq of APs (presynaptic) • More neurotransmitter released (presynaptic) • More neurotransmitter binds to receptors to open (or close) channels • Greater increase (or decrease) ion permeability • Greater (or lesser) ion flux • Greater depolarization

23. Inhibitory Synapses • Neurotransmitter binds to receptor. • Channels for either K or Cl open  hyperpolarizes the cell. • If K channels open, then…  K moves out  IPSP (inhibitory postsynaptic potential) • If Cl channels open, then either…  Cl moves in  IPSP  Cl stabilizes membrane potential.

24. Fast Inhibitory Synapses Involving K Channels

25. IPSPs are Grade Potentials • Higher freq of APs (presynaptic) • More neurotransmitter released (presynaptic) • More neurotransmitter binds to receptors to open (or close) channels • Greater increase (or decrease) ion permeability • Greater (or lesser) ion flux • Greater depolarization

26. Neural Integration • Divergence/convergence • Summation • The summing of input from various synapses at the axon hillock of the postsynaptic neuron to determine whether the neuron will generate action potentials

27. Divergence

28. Convergence

29. Convergence of Input as a Factor in Summation

30. Temporal Summation from the same Synapse

31. Spatial Summation from Different Synapses

32. Neurotransmitters • Acetylcholine • Biogenic Amines • Amino Acid Neurotransmitters • Neuropeptides • Autonomic Nervous Sysntem

33. Acetylcholine • Found in the CNS and PNS • Most abundant neurotransmitter in PNS. • Synthesis - Acetyl CoA + choline acetylcholine +CoA - Synthesized in cytoplasm of axon terminal - Biosynthetic enzyme: cholineacetyltransferase (CAT) • Breakdown - Acetylcholine  acetate + choline - Degradation occurs in synaptic cleft - Degradative enzyme: acetylcholinesterase (AchE)

34. Cholinergic Synapse

35. Cholinergic Receptors • Nicotinic - Ionotropic - Found mostly in the skeletal muscle - Some found in the CNS • Muscarinic - Metabotropic - Found mostly in the CNS

37. Actions at Nicotinic Cholinergic Receptors

38. Actions at Muscarinic Cholinergic Receptors

39. Biogenic Amines • Derived from amino acids • Catecholamines – derived from tyrosine - Dopamine - Norepinephrine (noradrenaline) - Epinephrine (adrenaline) • Norepineprine and epinephrine bind adrenergic receptors - Alpha and beta adrenergic receptors - Slow responses at all adrenergic receptors • Adrenergic receptors are G-protein-coupled • Generally linked to second messengers

40. Dopamine • Category: biogenic amine • Postsynaptic effect: Excitatory or inhibitory Fig. 6.11

41. Dopamine Receptors • Large diversity of metabotropicdopamine receptors (at least 6). • Bound by many antipsychotic drugs Kandel, 2000

42. Norepinephrine • Category: biogenic amine • Formed from dopamine • also in PNS • sympathetic NS

43. Norepinephrine Receptors • Effect depends on receptor bound • α-receptors α1- vs. α2-receptors (see next slide) • ß-receptors Silverthorn 2004

44. Receptors can be Located Presynaptically too – This will determine their effect Presynaptic GABAB receptor actions Isaacson, J Neuophysiolgy, 1998

45. Epinephrine • Category: biogenic amine • synthesized from norepinephrine • Effect depends on receptor bound • α-receptors • ß-receptors

46. Histamine • Category: biogenic amine • Postsynaptic effect: Excitatory Fig. 6-12

47. Histamine effects • Receptors are all G-protein coupled • In brain, affects arousal and attention • In periphery affects inflamation, vasodilation. • Why do some cold medicines make you sleepy? (good exam question).

48. Serotonin (5-HT) Category: Biogenic amines • Postsynaptic effect: Excitatory

49. Serotonin effects • Involved in sleep/wakefulness cycle • Most receptors are metabotropic, but one group are ionotropic. • Why does turkey make you sleepy? • SSRI and depression

50. Amino Acid Neurotransmitters • Amino acid neurotransmitters at excitatory Synapses: glutamate • Amino acid neurotransmitters at inhibitory Synapses: GABA (gamma-amino butyric acid)