Intro to CNS pharmacology

Question 1

Regarding ion channels: What do they feature on their extracellular and intracellular faces?

Answer 1

Saccharides extracellularly, kinase consensus sequences intracellularly.

Question 2

Recall some ion channel gating mechanisms.

Answer 2

Voltage-gating (membrane potential), ligand-gating (neurotransmitters), internal signaling.

Question 3

What is a leak channel?

Answer 3

A channel that is open at resting potential, which may be passive or active.

Question 4

What are the equilibrium potentials for the following ions: Na⁺, K⁺, Cl^-? How do these contribute to neuronal resting potential?

Answer 4

K^{<span>+</span>} = -75mV

Na⁺ = +55mV

Cl^- = -69mV

Since potassium has the highest resting conductance, it has the greatest contribution to resting potential.

Question 5

Which ion has the highest intracellular concentration: K⁺, Na⁺, Cl^-?

Answer 5

Potassium.

Question 6

What is the amplitude and duration of an action potential?

Answer 6

100mV; 1-10ms.

Question 7

How are the potassium channels involved in action potentials triggered to open?

Answer 7

Voltage-gating. They respond to the same depolarization that the sodium channels do, but are slower.

Question 8

How can an EPSP be generated without promoting influx of a cation?

Answer 8

By decreasing the conductance of a potassium leak channel. (This can be direct GPCR action or via PKA activation)

Question 9

What is the effect of GABA receptor activation?

Answer 9

Generation of IPSP, via increased conduction of chloride ion.

Question 10

Order the following enzymes according to their sequence of action in norepinephrine synthesis: DOPA decarboxylase, Dopamine beta-hydroxylase, Tyrosine hydroxylase. Which is located within granules?

Answer 10

1. Tyrosine hydroxylase to form L-Dopa.
2. Dopa decarboxylse to form Dopamine.
3. Dopamine b-hydroxylase to form norepinephrine.

The final reaction occurs within granules, and so dopamine b-hydroxylase can be found in the cleft.

Question 11

Describe the kinetics of the rate-limiting step of NE synthesis. How is it regulated?

Answer 11

Tyrosine hydroxylase is limited by BH4, and has higher affinity for it when phosphorylated. High neuronal activity promotes CaM phosphorylation; low cAMP reduces PKA phosphorylation (feedback via NE?)

Question 12

Describe the three mechanisms of NE release.

Answer 12

1. Calcium-dependent exocytosis (typical)
2. Reversal of membrane pumps (eg amphetamine)
3. Dendritic release

Question 13

What are the signaling pathways activated by the alpha-1, alpha-2, and many beta receptors?

Which can be found pre-synaptically?

Answer 13

Alpha-1 >> Gq

Alpha-2 >> Gi

Beta >> Gs

Alpha-2 (feedback) and Beta (feedforward) act as autoreceptors.

Question 14

How is synaptic NE inactivated?

Answer 14

1. Diffusion away from the cleft
2. Uptake pre-synaptically or by nearby non-neuronal cells (NET, Na⁺symport, etc)
3. Degradation by MAO/COMT

Question 15

Describe the synthesis and structure of neurotensin.

Answer 15

A 170-AA precursor is synthesized in the ER, then cleaved by peptidases in the Golgi to form neurotensin (13-AA) and neuromedin N.

Question 16

Describe the purpose of neurotransmitter co-release.

Answer 16

If the neurotransmitters are not redundant, more information can be specified. Different targets can be involved.

Question 17

Contrast the storage and release of neurotensin with other typical neurotransmitters.

Answer 17

Neurotensin vesicles are larger and denser, and are less concentrated at nerve terminals. This is because they can be released away from the active zone, although this requires more calcium >> high intensity activation.

Question 18

Contrast the signaling and inactivation of neurotensin with other typical neurotransmitters.

Answer 18

Inactivation is less intense, diffusion away more common. The result is longer, more distant targeting. The low concentration at the neurotensin receptor is compensated for by higher affinity (larger size, greater bonding).