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 Receptors Sensitization
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. αs αs β γ γ β αs GTP NE + GDP cAMP GDP ATP cAMP i3 loop GTP GDP
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)
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)
6) After hydrolysis of GTP to GDP, the αs subunit 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)
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)
β-adrenergic receptor
GTP αs
TM1
TM5
TM4
TM3
TM2 N
TM7
TM6
Asp - N
Extracellular space
TM3
TM2
TM4
Asp -
TM1
NE +
TM5
TM7
TM6
GDP αs AC β γ
cAMP γ β AC αs
GDP C
ATP
cAMP
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: choline acetyltransferase (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 metabotropic dopamine 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)

51. Glutamate Category: small-molecule Glutaminergic neurons
Postsynaptic effect: depends
Very important in CNS
Synthesized from glutamine from glia
Fig. 6.6

52. Glutamate Receptors Ionotropic Metabotropic NMDA AMPA kainate
late EPSP
Glycine & Mg2+ dependent
AMPA
early EPSP
kainate
Metabotropic
Kandel 2000

53. GABA (γ-aminobutyric acid)
Category: small-molecule
GABAergic neurons
Postsynaptic effect: Inhibitory
Made from glucose
Fig. 6.8

54. GABA Receptors GABAA – Ionotropic GABAB – Metabotropic
gates Cl- channel
GABAB – Metabotropic
gates K+ channel
Fig. 6.9

55. Neuropeptides Short chains of amino acids E.G., endogenous opiates
- endorphins – found in the brain, morphine-like
- Vasopressin – Anjtidiuretic hormone (ADH) – found in the posterior pituitary

56. Autonomic Nervous System (ANS)
Both branches of the ANS innervate most effector organs
Primary function – regulate organs to maintain homeostasis
Parasympathetic and sympathetic activities tend to oppose each other
- Parasympathetic Nervous system – rest
- Sympathetic nervous system – fight or flight response

58. Autonomic Pathways

59. Neurotransmitters and their Receptors in the ANS