Ionotropic and Metabotropic Receptors

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

Recall where chemical synapses are found?

Recall the Chemical Synapse?

Communication Across a Synapse

1. Action Potential

2. Voltage-gated Ca channels open

3. Ca triggers exocytosis

4. Nt diffuses and binds to receptor

5. Response in cell

Response is terminated by removing nt from synaptic cleft

6. Degradation

7. Reuptake

8. Diffusion

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).

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.

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.

Ionotropic ReceptorsSensitization

Ion Flow

Time, ms, in exposure to neurotransmitter

High

Low

Ionotropic Receptors

• Can have multiple binding sites for various neuromodulators.

• Can enhance or inhibit binding of endogenous ligands.

• Are good targets for drugs.

Fast Responses at Ionotropic Receptors

Metabotropic Receptors

• Most common type of receptor.

• Coupled to G protein.• No direct control of ion

channels.• Second messengers.

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.

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)

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)

5) Activated adenyl cyclase produces many molecules of cAMP from ATP.

(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)

GDPGTP

TM1

TM5

TM4TM3

TM2Asp -

NE +

N

C

β-adrenergic receptor

TM7 TM6

Gs

protein

GDP

αsAC

i3 loop GTPα s

TM1

TM5

TM4TM3

TM2

N

TM7 TM6

Asp -

βγ

ATP

cAMP

GDPαs

ACβγ

cAMPcAMP

cAMP

Cytoplasm

Extracellular space

Slow Responses at Metabotropic Receptors: Direct G-Protein Coupling

Slow Responses at Metabotropic Receptors: Second Messenger Coupling

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: HypoerpolarizationMembrane Stabilization

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)

Fast EPSPs

Slow EPSPs

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

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.

Fast Inhibitory Synapses Involving

K Channels

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

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

Divergence

Convergence

Convergence of Input as a Factor in Summation

Temporal Summation from the same Synapse

Spatial Summation from Different Synapses

Neurotransmitters

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

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)

Cholinergic Synapse

Cholinergic Receptors

• Nicotinic- Ionotropic- Found mostly in the skeletal muscle- Some found in the CNS

• Muscarinic- Metabotropic- Found mostly in the CNS

Actions at Nicotinic Cholinergic Receptors

Actions at Muscarinic Cholinergic Receptors

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

Dopamine

• Category: biogenic amine• Postsynaptic effect: Excitatory or inhibitory

Fig. 6.11

Dopamine Receptors

• Large diversity of metabotropic dopamine receptors (at least 6).

• Bound by many antipsychotic drugs

Kandel, 2000

Norepinephrine

• Category: biogenic amine• Formed from dopamine• also in PNS– sympathetic NS

Norepinephrine Receptors

• Effect depends on receptor bound– α-receptors

α1- vs. α2-receptors (see next slide)

– ß-receptors

Silverthorn 2004

Receptors can be Located Presynaptically too – This will determine their effect

Presynaptic GABAB receptor actions

Isaacson, J Neuophysiolgy, 1998

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

Histamine• Category: biogenic amine• Postsynaptic effect: Excitatory

Fig. 6-12

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).

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

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

Amino Acid Neurotransmitters

• Amino acid neurotransmitters at excitatory Synapses: glutamate

• Amino acid neurotransmitters at inhibitory Synapses: GABA (gamma-amino butyric acid)

Glutamate• Category: small-molecule• Glutaminergic neurons• Postsynaptic effect:

depends• Very important in CNS• Synthesized from

glutamine from glia

Fig. 6.6

Glutamate Receptors

• Ionotropic– NMDA• late EPSP• Glycine & Mg2+ dependent

– AMPA• early EPSP

– kainate• early EPSP

• Metabotropic

Kandel 2000

GABA (γ-aminobutyric acid)

• Category: small-molecule• GABAergic neurons• Postsynaptic effect:

Inhibitory• Made from glucose

Fig. 6.8

GABA Receptors

• GABAA – Ionotropic– gates Cl- channel

• GABAB – Metabotropic– gates K+ channel

Fig. 6.9

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

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

Autonomic Pathways

Neurotransmitters and their Receptors in the ANS