Lecture 15: Neurotransmitter Receptors and Signal Transduction

What do plasma membrane receptors determine?

the nature of the response of a neuron/muscle cell to NT

What are the two basic types of responses to plasma membrane receptors?

1.) opening of ion channels (Ionotropic receptors)

2.) alteration of concentration of intracellular metabolites (metabotropic receptors)

What are ionotropic receptors?

membrane-bound protein complexes that form an ion-permeable pore in the membrane

What are metabotropic receptors?

the alteration of the concentration of intracellular metabolites

what is response magnitude determined by?

1.) receptor density
2.) state of the receptors
3.) amount of NT released

What are agonists?

agonists bind to receptors and activate it to produce a biological response

what are antagonists?

antagonists bind to the receptor and inhibit its function.
blocks the action of the agonist

What two ways are how receptors can be activated?

receptors can be activated by either endogenous agonists (NTs or hormones) or exogenous agonists (drugs), resulting in a biological response

what do agonists possess?

affinity (potency) and intrinsic activity (response of efficacy)

what do antagonists possess?

affinity (potency) but no efficacy of its own

what is an inverse agonist?

inverse agonists bind to the receptor but produce an intrinsic activity (efficacy) in the opposite direction

what are the two main types of NT receptors?

1. ionotropic receptors
2. metabotropic receptors

inotropic receptors include what two families?

1. nicotinic receptor family (nAChR family)
2. ionotropic glutamate receptor (igluR)

What receptors are included in the nAChR family?

nAChR, GABA-A receptors, Glycine receptors, and a subclass of %HT

What is nAChR?

nicotinic acetylcholine receptor (nAChR) is a heteromeric protein complex composed of 5 subunits (2α, β, γ and δ)

What is a protein subunit?

A single protein molecule that assembles (or coassembles) with other protein molecules to form a protein complex (e.g. receptor)

What is the structure of a protein subunit?

The extracellular domains of the subunits come together to form a funnel shaped opening.
The center of the funnel narrows to form the domain of the receptor that determines the open and closed state of the ion pore.

What is the function of the central domain of nAChRs?

To concentrate and force ions to interact with aminoacid in the limited space of the pore, allowing for ion passage without a barrier.

What is the role of the intracellular domains for nAChRs?

To form short exits and entrances for ions traveling into the cell, respectively.

What does each subunit of nAChRs consist of?

4 transmembrane segments (TM1-TM4)

What does transmembrane segments of nAChR subunits consist of?

hydrophobic amino acids that stabilize the domain within the lipid membrane.

What determines ion selectivity and current flow in nAChRs?

The structure of the channel pore

What specific membrane spanning segments line the pore of nAChR subunits?

5 TM2 regions

How are aminoacids that compose the TM2 region arranged?

aminoacids that make up the TM2 region is arranged so that 3 rings of negatively charged amino acids are facing toward the central pore.

What is the purpose of 3 negatively charged rings of aminoacids that make up the TM2 region?

Rings provide selectivity filter for cations

What is nAChR permeable to?

Na+, K+, and Ca2+ (monovalent ions are preferred)

How do the cations move through nAChR channels?

The cations move down their respective electrochemical gradients

How do the cations enter or exit through nAChR channels?

Cations enter or exit through the lateral openings present towards the cytoplasmic end. This is an additional filtering step.

What specific amino acid residues form parts of the nAChR negatively charged rings for ion selectivity?

Glutamate, leucine, serine, threonine residues form part of the negatively charged rings for ion selectivity

How does the opening of nAChR occur?

The opening of nAChRs occurs by the binding of 2 ACh molecules to the receptor to initiate concerted changes in its conformation.

What specific structural changes occur during the channel opening of nAChRs?

The binding of the two ACh molecules triggers the rotation of the TM2 segments, which opens up the channel.

How are nAChRs anchored to synapses?

Rapsyn anchors nAChR to synapses by interacting with intracellular domains

Why is nAChR clustering needed?

nAChR clustering is required to ensure efficient communication between presynaptic motor neuron and muscle cell

What is released from presynaptic motor neurons after nAChR clustering and what does it bind to?

Agrin is released from presynaptic motor neurons and binds to post synaptic membrane proteins after nAChR clustering

What is a common post-translational modification of nAChRs?

phosphorylation is a common post-translational modification of nAChRs

What 3 protein kinases is nAChR phosphorylated by?

cAMP-dependent PK (PKA)
Ca-phospholipid-dependent PK (PKC)
Tyrosine kinase (TK)

What does phosphorylation of nAChRs account for?

The phosphorylation of nAChRs accounts for rapid desensitization of these receptors

What are the subunits of neuronal nAChRs?

α and β

What are the types of neuronal nAChRs?

homomeric (composed of identical subunits) or hetermeric (composed of different subunits)

What are the most common types of neuronal nAChR?

α 7 nAChRs (low-affinity)α4 β2 nAChRs (high-affinity)

What other ionotropic receptors are similar to nAChRs?

Serotonin 5HT3 receptor
GABA-A receptors (pentameric complex)
Glycine receptors
Puringeric Receptors

What is the serotonin 5HT3 receptor?

Ionotropic receptor that is permeable to Na and K ions but is impermeable to Ca. The opening of the channel after agonist binding is much slower compared to nAChRs.

What is the GABA-A receptor?

Pentameric ionotropic receptor

What does the opening of the channel of the GABA-A receptors produce?

Opening of channel produces hyperpolarization of chloride influx (aka anion channel), provided by positively charged amino acids near the pore

GABA-A receptors are what kind of protein and how are its properties modulated?

GABA-A receptors are allosteric proteins and its properties are modulated by barbiturates and benzodiazepines

What is the role of picrotoxin in GABA-A receptors?

Picrotoxin is a convulsant that binds to the channel pore and prevents chloride ion flow

What is the role of bicuculline in GABA-A receptors?

Bicuculline is a convulsant that acts as an antagonist for GABA-A receptors

How are GABA-A receptors modulated?

phosphorylation

What are Glycine receptors?

Major inhibitory ionotropic receptors in spinal cord and brain stem, and their anionic selectivity is similar to GABA-A receptors.

What clusters GABA and Glycine receptors?

Gephryin

What are Purinergic receptors?

Purinergic receptors are ionotropic receptors that bind to ATP or adenosine