Lecture 7 - Neuro 4; Ligands, Acetylcholine, and Norepinephrine

Past lecture summary

• Soma + Dendrites = Ligand-gated channels and metabotropic receptors

• Axon hillock = lots of Voltage-gated Na+ and K+ channels since need graded potentials to be large enough to reach threshold potential to fire an AP

• Axon = lots of voltage-gated Na+ and K+ voltage-gated channels in Nodes of Ranvier

• Terminal = Ca2+ channels and Ca2+ pump

  • Calcium rushed in, then pumped out

Ligand

• Chemical messenger that interacts with a receptor

  • Neurotransmitter (NT) is a specific type of ligand

Receptor

• Protein that binds to a ligand a communicates a signal via biochemical pathways inside the cell

• Most receptors for NT are embedded in the membrane

• Have an NT-specific ligand-binding domain

• Intracellular function domain - determines effect of the ligand binding to the receptor

Ligand vocab

• Endogenous

• Agonist

• Antagonist

Endogenous

• Found in the body, the natural ligand

  • Not something like Coffee - comes from outside

Agonist

• Mimics the natural ligand ; binds and activates the receptor

• Agonists generally produce similar types of physiological effects by binding to and activating receptors, mimicking natural ligands to initiate a biological response. However, they do not always cause the same intensity of effects

Antagonist

• Binds, but doesn’t activate the receptor ; may block other ligands from binding

Ligand-receptor interactions - Law

• Ligand and receptors bind to each other = Ligand-receptor complex

  • Ligand-receptor complex is reversible

• Think of their interactions through the Law of Mass Action

  • The rate of reaction (rate of creating the complex and then giving a response) is proportional to the mass of the reactants

  • Can then increase response by:

    • Increasing number of receptors

      • More possible binding sites

    • Increase mass (number) of ligand

      • Because ligand-receptor complex can spontaneously unbind, more ligand will increase the likelihood of getting binding and then getting a response

Neurotransmitters

• 50 substances

  • They are:

    • Synthesized in neurons

    • Released from presynaptic cells following depolarization

    • Bind to a postsynaptic receptor and cause an effect

      • Change in membrane potential (±)

        • Depolarization change: ESPS

        • Hyperpolarizating effect: IPSP

Neurotransmitter and receptor diversity

• Axes of diversity:

  • What is it?

    • Amino acids

    • Biogenic amines (from amino acids)

    • Neuro peptides (proteins)

    • *Acetylcholine

    • *Adenosine

    • *Nitric oxide

  • Where is it?

  • What effect does it have?

• A single neuron can produce and release more than 1 neurotransmitter, but they usually use just one

  • Genetically determined, no spontaneous switching

  • Their synaptic machinery (enzymes, transporters, vesicle proteins) is optimized for that transmitter

  • Postsynaptic targets are wired to expect that specific chemical signal

A single neurotransmitter can have very different effects on target cells

• Different receptors to the same neurotransmitter can have opposite effects

• Multiple receptors to a single neurotransmitter could be excitatory, or inhibitory, or both

• The neurotransmitter AND the receptor determine what the effect on the postsynaptic cell will be

• Ex: Glutamine can depolarize and hyperpolarize

Receptor classification (2)

• Ionotropic

• Metabotropic

Ionotropic receptors

• Ion channel receptors

  • NT binds, ion channel opens, ions cross into neuron, change in membrane potential

Metabotropic receptors

• NT binds to receptor, binding causes a signal transduction pathway which opens an ion channel separate from the receptor

  • Modifies existing proteins, activates or releases gene expression

  • Coordinated cellular response

Which of the following receptors is most likely an Na+ Channel?

• AMPA

  • Ionotropic and Excitatory

NT: Acetylcholine (ACh)

• Synthesized at axon terminal of “cholinergic” neurons

  • Adjective version of Acetylcholine

• NT at neuromuscular junction and parts of central and peripheral nervous systems

• ACh has 2 types of receptors (AChR):

  • Ionotropic receptor: Nicotinic AChR

  • Metabotropic recteptor: Muscarinic AChR

Nicotinic AChR

• Also activated by nicotine

  • Nicotine is an agonist for this receptor

• Ionotropic

• Found on skeletal muscle, autonomic neurons, and CNS

• Non-specific cation channel

  • Permeable to Na+, K+, and sometimes Ca2+

    • Na+ mostly moves through because it has a super high driving force

  • Excitatory

Myasthenia gravis and the Law of Mass Action

• Myasthenia gravis is characterized by muscle weakness due to loss of nAChRs (Nicotine)

  • Ligand present, but less receptors → decrease in ligand-receptor complexes → decreased response

    • Involves inotropic receptors

  • Presynaptic ACh release is normal, postsynaptic response is reduced

• Treated with Acetylcholine esterase (AChE) inhibitors to prevent degradation of ACh in the synapse

  • AChE splits ACh into acetate and Choline, ending transmission → we don’t want this, so we inhibit it

  • We can’t easily increase receptors, so we increase ligand / prevent its breakdown

    • More ligand (stop it from being degraded, slight increase in ligand-receptor complex, restore muscle response

Muscarinic AChR

• Also activated by muscarine (agonist)

• Metabotropic

  • G-protein coupled receptors (GPCR)

• Found in smooth/cardiac muscles, glands, and CNS

• Excitatory or inhibitory (depending on receptor type)

Summary for Cholinergic receptors

• Nicotine - nAChR

• Muscarine - mAChR

Norepinephrine

• Catecholamine synthesized from amino acid Tyrosine

• Related to Dopamine and Norepinephrine (NE)

• Used throughout the body for diverse and sometimes opposite effects

• Binds to adrenergic receptors which are metabotropic

  • Alpha (a1 and a2)

  • Beta (B1 and B2)

    • No ionotropic receptors

    • Ignore B2 for now

Effect of Adrenergic receptors

• Depends on the G protein they’re coupled to:

  • a1 → Gq

    • Gq “quirky”

  • a2 → Gi

    • Gi inhibits

  • B1 → Gs

    • Gs stimulates

B1 receptor and Gs

• When norepinephrine binds to B1 receptor, activates Gs protein

• Gs protein has 3 subunits:

  • Alpha subunit + 2 others

• Alpha subunit of Gs protein dissociate from the other 2 and talks to enzyme adenyl cyclase

• Adenyl cyclase turns ATP into cyclic AMP (messenger)

• Cyclic AMP activates Protein Kinase A (PKA)

• PKA phosphorylates - activates Ca2+ channel, making them easier to open, and cell becomes more excitable

A2 receptor and Gi

• When norepinephrine binds to A2 receptor, activates Gi protein

• Gi protein has an Alpha subunit

• Alpha subunit of Gi protein dissociate from the other 2 and binds to enzyme adenyl cyclase, inhibiting it

• Decreased cyclic AMP = decreased PKA = less phosphorylation

• Ca2+ channels are harder to open, Ca2+ levels decrease, and cell becomes less excitable

A1 receptor and Gq

• When norepinephrine binds to A1 receptor, activates phospholipase C

• Phospholipase C breaks down lipid PIP into IP3 and DAG, which act as messengers

• DAG activates protein kinase C

• Protein kinase C phosphorylates Ca2+ channels, which make the cell more excitable

Adrenergic Receptors Summary