Neurotransmitter Receptors

Question 1

Postsynaptic NT Receptor Categories

Answer 1

o Ionotropic – act through direct gating – faster acting; 2 NTs bind directly to an ion channel
 Depolarization if permeable to Na+
 Hyperpolarization if permeable to Cl-
o Metabotropic – act through indirect gating – slower and longer lasting; ONE protein/domain
 NT binds to receptor  activates G proteins  intracellularly activates nearby channel
 Stimulatory or inhibitory

Question 2

General Principles of NT Receptors

Answer 2

o High degree of specificity
o Selectivity of the ion channel determines whether the effect will be inhibitory or stimulatory
o Kinetics of transmitter binding determines length of channel opening and duration of effect
o Single NT can activate more than one receptor since they are expressed as multiple subtypes
o Single NT can activate receptors that are either ionotropic or metabotropic

Question 3

Ionotropic Receptors

Answer 3

o	Nicotinic ACh (nACh) – ACh – Na+ and small amount of Ca2+ ions
o	AMPA – Glutamate – Na+ ion
o	NMDA – Glutamate – Na + and Ca2+ ions
o	Kainate – Glutamate – Na+
o	5-HT3 – serotonin – Na+
o	GABAA – GABA – Cl-
o	Glycine – Glycine – Cl-

Question 4

Two Major Families of Ionotropic Receptors - based on structural similarities

Answer 4

o Family 1 – nACh, GABAA, 5-HT3, Glycine
 4 transmembrane helices per subunit; 5 subunits
 Both N and C-terminal domains are extracellular
o Family 2 – Glutamate receptors (AMPA, NMDA, Kainate)
 3 transmembrane helices plus Pore loop per subunit; 5 subunits
 Cytoplasmic C-terminal tail contains sites for phosphorylation and binding of intracellular proteins

Question 5

nACh Receptor

Answer 5

o TWO ACh binds to extracellular N terminus of the 2 alpha subunits  causes channel to open
o Structural diversity produces channels with unique properties (desensitization rates and permeability to calcium)
o Cation channel with varying permeability to Ca2+
o Intracellular loop contains serine and tyrosine phosphorylation sites

Question 6

GABAa Receptor

Answer 6

o Major mediator of inhibitory synaptic transmission in the brain
o Same structure as nACHh receptor EXCEPT opening of channel increases permeability of Cl- ions resulting in hyperpolarization
o Muscular GABA receptors can have any combination of subunits
o Neuronal/CNS GABA receptors MUST have at least 2 alpha subunits
o TWO GABA molecules must bind to open the channel
o some CNS depressant drugs produce allosteric potentiation of GABA’s effects

Question 7

Glutamate Ionotropic Receptor Characteristics

Answer 7

o Major mediator of excitatory synaptic transmission in the brain and spinal cord
o Structurally distinct from nACH and GABA receptors
o 3 subunits completely transverse the membrane and on forms incomplete pore loop
o Tetramers or pentamers composed of 2 different subunits
o AMPA and NMDA receptors co-exist in glutamate CNS synapses

Question 8

Glutamate Ionotropic AMPA Receptor

Answer 8

 Fast kinetics
 Permeable to Na+ and K+
 Desensitized rapidly

Question 9

Glutamate Ionotropic NMDA Receptor

Answer 9

–ligand gated AND voltage dependent ion channel
 slower kinetics
 permeable to Na+, K+ and Ca2+
 Ca2+ activation of intracellular signaling pathways
 Requires co-agonist glycine to open channel
 Requires an initial depolarization to remove Mg2+ blockade of channel
 Involved in development, learning, memory, and neurotoxicity (stroke, seizures, traumatic CNS injury, neurodegenerative diseases

Question 10

Metabotropic Receptor Characteristics

Answer 10

o Enormous number of receptors that can be activated by many NTs
o Produce intracellular signals upon NT interaction with receptor
o Typically slower than ionotropic receptors  must interact with G proteins
o Most small molecule transmitters bind to BOTH ionotropic and metabotropic receptors

Question 11

G-protein Association with Metabotropic Receptors

Answer 11

o G proteins move along the intracellular face of the membrane
o Transmitter binding causes conformational change in receptor and activation of G protein by exchanging inactive GDP form for active GTP form
o Activated G protein splits and subunits (alpha, gamma, beta) can activate membrane bound enzymes/effector proteins to initiate a cascade of effects
 Galpha subunit removes phosphate from GTP to terminate its own activity
o SHORT CUT: G protein subunits can directly activate ion channels
o NTs activate different G proteins and 2nd messenger systems (Ca2+, cAMP, cGMP, IP3, DAG)

Question 12

Norepinephrine Metabotropic Receptor

Answer 12

– can be coupled to different G proteins

o Activates Gs protein  adenylyl cyclase  cAMP  protein kinase A  increases protein phosphorylation

Question 13

Glutamate Metabotropic Receptor

Answer 13

o Activates Gq protein  phospholipase C  diacylglycerol and IP3  protein kinase C and Ca+ release  increase protein phosphorylation and activate calcium-binding proteins

Question 14

Dopamine Metabotropic Receptor

Answer 14

o Activates G-inhibitory protein that inhibitis  adenylyl cyclase  cAMp  protein kinase A  thus decreases protein phosphorylation

Question 15

Metabotropic Receptor Response Depends on:

Answer 15

o Type of receptor activated
o Type of G proteins present
o Effector enzymes present
o Metabotropic receptor subtypes for a single NT can activate different types of G proteins
o Activation of a single receptor can result in the activation of many G protein molecules  amplification of signal AND long term effects