Neuroscience/Objectives/Lecture 6

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Contents 1 Neurotransmitter receptors 1.1 DEFINE receptor, binding site, agonist, antagonist, allosteric modulation. 1.2 DEFINE ionotropic and metabotropic receptors. 1.3 OUTLINE receptors based on their signal transduction mechanism. 1.4 DESCRIBE the overall structure of ionotropic receptors and mechanisms which contribute to their stimulatory or inhibitory activity. 1.5 DESCRIBE the differences between NMDA and AMPA/kainate receptors. 1.6 LIST drugs that act at ionotropic receptors and diseases arising due to alterations of ionotropic receptor signaling. 1.7 DESCRIBE the general structure of metabotropic receptors and G proteins. 1.8 LIST the metabotropic receptors, their associated G proteins, and their second messenger systems. 1.9 OUTLINE the signal transduction system of the β-adrenergic receptor, muscarinic acetylcholine receptor, and the histamine receptor. 1.10 DESCRIBE the activation of ion channels by second messengers 1.11 DESCRIBE the long-term effect of synaptic transmission by metabotropic receptors. 1.12 LIST drugs that act at metabotropic receptors and diseases arising due to alterations of metabotropic receptor signaling.

Neurotransmitter receptors

DEFINE receptor, binding site, agonist, antagonist, allosteric modulation.

Receptor

A receptor is a protein that binds a ligand and transduces a signal, inducing a change in cellular function.

Binding site

A binding site is an area on the receptor capable of binding ligand.

Agonist

Agonists are chemicals that bind to the receptor and produce the same effects as the endogenous ligand.

Antagonist

Antagonists are inherently inert except that they block the effects of the agonist by binding its receptor.

Allosteric modulation

Allosteric modulation is modulation that occurs through the binding of a ligand at a site distinct from the endogenous ligand's binding site.

DEFINE ionotropic and metabotropic receptors.

Ionotropic receptors

are ligand-gated ion channels that respond to

ligand binding by opening their channels and passing current. They are very fast, producing postsynaptic potentials (PSPs) very rapidly (excitatory PSPs if permeable to sodium, inhibitory PSPs if permeable to chloride).

Metabotropic receptors

are associated with G proteins (inhibitory or stimulatory), which are themselves coupled with distinct ion channels through second messenger systems (e.g. cAMP). Their reliance on second messengers makes them inherently slower but longer-lasting and more diverse than ionotropic receptors.

OUTLINE receptors based on their signal transduction mechanism.

Metabotropic= G-protein coupled
Ionotropic= ligand gated cation channel

DESCRIBE the overall structure of ionotropic receptors and mechanisms which contribute to their stimulatory or inhibitory activity.

Ionotropic receptors contain 4-5 subunits arranged around an ion pore. Each subunit spans the membrane 3 or 4 times. The selectivity of the pore for ions is dependent on the structures of these membrane-spanning domains. If the ion channel is permeable to sodium, then the ionotropic receptor will be excitatory; if it is permeable to chloride, then it will be inhibitory. (Ions flow down their concentration gradients.)

DESCRIBE the differences between NMDA and AMPA/kainate receptors.

Both NMDA and AMPA/kainate receptors are ionotropic, and both are ligand-gated by the neurotransmitter glutamate. However, the NMDA receptor is also voltage-gated, requiring strong postsynaptic depolarization in order to relieve the tonic blockade of its intrinsic ion channel by magnesium.

In addition, while all three receptors are permeable to sodium and potassium, only the NMDA receptor is also permeable to calcium. The NMDA receptor also exhibits slower kinetics, and requires a coagonist glycine to open the channel.

LIST drugs that act at ionotropic receptors and diseases arising due to alterations of ionotropic receptor signaling.

Benzodiazepines, barbituates, and ethanol all bind the GABA receptor and potentiate its effects by prolonging the time its intrinsic channel is open. Overall, they repress synaptic transmission, suppress neuronal excitability, and reduce seizure and anxiety.

Myasthenia gravis results from the presence of antibodies against muscle nAChR.

Myasthenic syndromes result from mutations in the muscle nAChR.

Neurotoxicity is caused by excessive glutamate, which is toxic to neurons at high levels. This contributes to neural injury during stroke, repeated seizures, and traumatic injuries.

DESCRIBE the general structure of metabotropic receptors and G proteins.

Metabotropic receptors, like all G protein-coupled receptors, are 7-transmembrane receptors composed of a single polypeptide chain. Its N-terminus is extracellular and its C-terminus is intracellular.

G proteins (GTP/GDP-binding proteins) are intracellular heterotrimeric proteins (α, β, γ) coupled with metabotropic receptors. They transduce signals from the receptor to a downstream target molecule.

LIST the metabotropic receptors, their associated G proteins, and their second messenger systems.

Receptor	G protein	Second messenger system
α2-adrenergic R	Gi	↓AC -> ↓cAMP -> ↓PKA
β-adrenergic R	Gs	↑AC -> ↑cAMP -> ↑PKA
mGluR	Gq	↑PLC -> ↑IP3 + ↑DAG -> ↑PKC
D2R	Gi	↓AC -> ↓cAMP -> ↓PKA
mAChR	Gq	↑PLC -> ↑IP3 + ↑DAG -> ↑PKC
HR (histamine)	Gγ	↑PLA2 -> ↑Arachidonic acid -> ↑Prostaglandin synthetic enzymes

OUTLINE the signal transduction system of the β-adrenergic receptor, muscarinic acetylcholine receptor, and the histamine receptor.

β-Adrenergic receptor:

• Norepinephrine (NE) binds β receptor
• Induced conformational change in receptor causes associated G_s protein to release GDP and bind GTP
• Activated G_α subunit dissociates from heterotrimeric G protein complex and activates nearby adenylyl cyclase (AC)
• AC enzymatically converts ATP into cAMP
• cAMP activates cAMP-dependent protein kinase (PKA)
• PKA phosphorylates downstream target proteins

Muscarinic AChR:

• ACh binds mAChR
• Induced conformational change in receptor activates adjacent G_q protein
• G_α subunit dissociates and activates PLC
• PLC hydrolyzes PIP₂ into IP₃ and DAG
• IP₃ stimulates release of Ca²⁺ from intracellular stores
• DAG and Ca²⁺ activate PKC
• PKC phosphorylates downstream target proteins and enhances expression of Ca²⁺-binding proteins

Histamine receptor:

• Histamine binds receptor (HR)
• Induced conformational change causes dissociation of G_α subunit, leaving G_β and G_γ subunits behind
• G_γ subunit activates PLA₂
• PLA₂ catalyzes the conversion of phospholipids into arachidonic acid
• Arachidonic acid (a precursor for prostaglandin synthesis) stimulates the expression of prostaglandin synthetic enzymes (e.g. COX)

DESCRIBE the activation of ion channels by second messengers

Second messengers can result in the activation of ion channels. For example, activation of the β-adrenergic receptor results in the activation of a G_αs protein subunit, which activates adenylyl cyclase, causing a rise in intracellular cAMP. cAMP activates PKA, which can then phosphorylate downstream proteins, such as potassium channels. It may also translocate to the nucleus where it can phosphorylate transcription factors (e.g. CREB) and enhance the expression of ion channels.

DESCRIBE the long-term effect of synaptic transmission by metabotropic receptors.

Activation of metabotropic receptors may result in alterations to gene expression, which lead to long-lasting physical changes to cells. Refer to the above example that includes CREB, a transcription factor regulated by PKA (through AC and cAMP), Ca²⁺ (through Ca+/calmodulin protein kinases), and MAPK (through Ras).

LIST drugs that act at metabotropic receptors and diseases arising due to alterations of metabotropic receptor signaling.

Drugs that act on metabotropic receptors

Drug	Target and effect
Atropine	mAChR antagonist
Isoproteronol	β-receptor agonist
Propranolol	β-receptor antagonist
Phentolamine	α2-receptor agonist

Diseases related to altered metabotropic signaling

Disease	Description
Cholera	Caused by cholera toxin from Vibrio cholerae; toxin binds to Gαs subunits and irreversibly activates them (preventing the dissociation of GTP), causing constitutive activation of chloride channels in the GI tract, resulting in excretion of excess Cl-, Na+, and water (secretory diarrhea).
Pertussis	Caused by pertussis toxin from Bortadella pertussis; toxin binds to and ADP-ribosylates the Gαi subunit, preventing the release of GDP, keeping it in the inactive state; this results in the enhanced potassium channel phosphorylation and activation.