Intro to CNS Pharmacology Flashcards
How have proteins evolved in function to allow ionic passage across the membrane?
- ATPase driven pumps
- Transporters
- Ion channels
Ion channels: some generalities
- Integral membrane proteins
- Multiple membrane-spanning domains
- Form a hydrophobic channel in the center
- Selective for ions and regulated by changes in the cellular environment
- Multiple gene products; multiple subunits
- Glycosylated on the extracellular side
- Consensus sequences for kinases
- Exhibit specificity for the ion(s) that permeates the channel
- Ionic movement is driven by its electrochemical gradient
Functional classification of ion channels based upon the gating mechanism:
- Passive: non-gated, always open
-
Active: are gated
- i.e. the closed and open states of the channel are regulated
Some types of gating include:
- membrane potential difference (voltage gated)
- small extracellular molecules (i.e. neurotransmitters)
- other membrane proteins
- e.g. beta-gamma subunits of G proteins
- Intracellular molecules
- e.g. ions, ATP
What is a leak channel?
channel is open at resting membrane potential
- Can be either active or passive
- All passive channels are leak channels
What is the resting membrane potential in neurons?
Em (or Vm) = -60 mV
What factors that give rise to the resting membrane potential?
- Intracellular proteins are predominantly anions
- Leak channels are present in the plasma membranes that allow for potassium and chloride movement across the membrane
- Conductance (g) of the membrane to K is 20 times greater than the conductance to Na
- As a result, there is an unequal distribution of Cl, K and Na across the membrane
Describe the distribution of Na+, K+ and Cl- across the membrane:
-
K+:
- high inside and low outside
-
Na+ and Cl-:
- high outside and low inside
Nernst potentials:
membrane potentials at which the ion is in
electrochemical equilibrium across the membrane
- EK = -75 mV
- ENa = +55 mV
- ECl = -69 mV
What can oppose the leak channels?
Na-K ATPase pump that moves Na ions
out of the cell and K ions into the cell
What causes action potentials in CNS neurons?
voltage operated sodium channels open in the membrane in response to localized depolarization
Action Potentials:
Properties
- Since V=IR, increased sodium current results in change in V
- Voltage gated potassium channels also open
- opening is more gradual
- inactivation is slower than sodium channels
- Action potentials are all or none
- Amplitude of about 100 mV
- 1-10 msec in duration
- Propagated through cycles of depolarization and repolarization
Synaptic potentials:
Properties
- Small, graded potentials that can lead to the initial depolarization that causes an action potential
- Local
- Can summate in time and space
- Only a few mV in size and a few msec in duration
Synaptic potentials:
Two Types
-
Excitatory, postsynaptic potential (EPSP)
- membrane potential becomes more positive
- if it increases enough, threshold will be reached
-
Inhibitory postsynaptic potential (IPSP)
- Membrane potential moves to more negative values
- Impacts a summating EPSP which will now not reach threshold
Two mechanisms by which an EPSP can occur:
-
Increased conductance
- Open a ligand gated ion channel for sodium or calcium
- Nicotinic cholinergic receptor
- Glutamate receptor
- Open a ligand gated ion channel for sodium or calcium
-
Decreased conductance
- Close a leak channel for potassium
- Usually due to changes in the phosphorylation of the channel
- regulated by second messenger cascades; GPCRs
- Close a leak channel for potassium
Mechanisms for the production of IPSPs:
-
Increased conductance of the membrane to either potassium or chloride
- Ligand gated chloride channel
- e.g. GABA receptor
- Ligand gated chloride channel
-
G protein coupled receptor activation can result in the opening of K channels
- Via direct interactions between the channel protein and G protein
- As a result of changes in phosphorylation state of closed K channels
- mediated by second messenger cascades
Norepinephrine:
CNS Distribution & Physiological Roles
- Noradrenergic neurons are located in the medulla oblongata, pons and midbrain
- Called the reticular activating system
- Very important in arousal (wakefulness) and in regulation of autonomic functions like breathing and blood pressure
How is norepinephrine synthesized?
- Precursor: tyrosine
- Tyrosine ⇒ 3,4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase
- DOPA is converted into dopamine by DOPA decarboxylase
- low substrate specificity
- Dopamine ⇒ norepinephrine by dopamine beta hydroxylase
- will oxidize almost any phenyl-ethylamine to the corresponding phenylethanolamine
Norepinephrine:
Regulation of synthesis
Primary regulation of norepinephrine synthesis occurs via tyrosine hydroxylase (TH)
- TH is normally saturated with tyrosine so its activity is the rate limiting step for DOPA synthesis under basal conditions
- TH has an essential co-factor tetrahydrobiopterine, BH4
-
Short-term regulation of tyrosine hydroxylase activity occurs via:
- phosphorylation at four different serine residues
-
end-product (i.e. norepinephrine) inhibition of BH4 binding to the enzyme
- detects over-filled vesicles
-
Long-term regulation occurs via new protein synthesis
- primarily increased amounts of tyrosine hydroxylase
Norepinephrine:
Regulation of storage and release
- Norepinephrine is found in vesicles along with the enzyme dopamine betahydroxylase
- Dopamine is taken into the vesicle, the last step of synthesis occurs there
- Vesicular monoamine transporters are called VMAT; VMAT2 is found in the brain
- Three mechanisms of norepinephrine release
- Release is regulated by presynaptic receptors (autoreceptors)
Three mechanisms of norepinephrine release:
- calcium-dependent exocytosis of vesicles
- reversal of plasma membrane transporters
- dendritic release that is not calcium-dependent
What are the autoreceptors that regulate norepinephrine release?
- alpha-2 receptor inhibits release
- beta receptor increases release
Norepinephrine:
Regulation of Inactivation
- All transmitters can be inactivated by diffusion
- Reuptake by the presynaptic neuron is the most important: neuronal not astrocytic
- Enzymatic inactivation
Describe the reuptake of norepinephrine in the presynaptic neuron:
- High affinity carrier proteins move norepinephrine from extracellular to intracellular compartments
- Energy requiring ⇒ sodium co-transporter
- Binding site for norepinephrine that is the site of action of inhibitors
- Once norepinephrine is intracellular, it can be re-packaged