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NEUR1005 > Post-synaptic drug targets: G protein-coupled receptors and effectors (Dr. Pitcher) > Flashcards

Post-synaptic drug targets: G protein-coupled receptors and effectors (Dr. Pitcher) Flashcards

1
Q

How many GPCR coding sequences does the human genome contain ?
How much of the cellular protein do these account for ?

A
  • 797 GPCR encoding sequences

- 1-5% of cellular protein

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2
Q

How many GPCRs:

  • are non-sensory ?
  • have known ligands ?
  • are targeted by prescription dugs ?
  • are being targeted in clinical trials ?
  • are “orphan GPCRs” ?
A
  • 363 non-sensory GPCRs
  • 240 have known ligands
  • 46 targeted by prescription drugs
  • 70 more targeted in clinical trial
  • 120 “orphan GPCRs”
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3
Q

What is an orphan GPCR ?

A

A GPCR w/ no known ligand.

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4
Q

What is the proportion of prescription drugs targeting GPCRs ?

A
  • ~40%
  • 6 of top 10 and 60 of top 200 best
    selling drugs target GPCRs
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5
Q

Where are GPCRs active ?

What pathologies are associated w/ their dysfunction ?

A
  • Active in every organ system
  • Dysfunction associated with most disease states
    including pain, asthma, obesity, cancer, cardiovascular, gastrointestinal and CNS diseases
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6
Q

Give some exemples of best selling GPCR targetting drugs.

A 
Claritin® (allergy) 
Zantac® (ulcers and reflux) 
OxyContin® (pain), 
Lopressor® (high blood pressure), 
Imitrex® (migraine headache), 
Reglan® (nausea) and
Abilify® (schizophrenia, bipolar disease and depression) 
Antihistamines, opioids, alpha and beta blockers, serotonergics and dopaminergics.
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7
Q

How much money was made in 2007 w/ GPCR targeting drugs ?

A

$23.5 billion

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8
Q

What are potential ligands for GPCRs ?

A

Biogenic amines: NA, DA, 5-HT, histamine, ACh,
AAs + ions: Glu, Ca2+, GABA
Lipid: LPA (Lipoprotein A), PAF (Platelet-activating Factor), prostoglandins, leukotrienes, anandamine, S1P (Sphingosine-1-phosphate)
Peptides: angiotensin, bradykinin, thrombin, bombesin, FSH, LH, TSH, endorpins
Others: light, odorants, pheromones, nt, opiates, cannabinoids

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9
Q

What are some of the bioloigical functions of GPCRs ?

A
  • Smell and taste
  • Embryogenesis
  • Perception of light
  • Development
  • Slow synaptic transmission
  • Cell growth and differentiation
  • Function of exocrine/endocrine glands
  • HIV infection
  • Chemotaxis
  • Oncogenesis
  • Exocytosis
  • Control of blood pressure
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10
Q

What kinds of GPCRs are known according to the different ligands that have been identified ?

A

Biogenic amines: adrenoceptors, muscarinic, and 5-HT receptors
AAs: metabotropic glutamate and GABAB receptors
Ions: Ca2+ receptor
Lipids: prostaglandin, thromboxane and PAF receptors
Neuropeptides: neuropeptide Y, opiate, cholecystokinin, VIP receptors
Peptide hormones: angiotensin, bradykinin, glucagon, calcitonin receptors
Glycoproteins: TSH, LH/FSH receptors
Proteases: thrombin receptor
Light: Rhodopsin

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11
Q

What is the general structure of 7TM receptors/heptahelical receptors ?

A
  • extracellular -N terminus
  • intracellular -C terminus
  • N-glycosylated extracellular domain
  • 7TM regions
  • disulfide bonds between extracellular loops 2 and 3
  • larger intracellular domain for heterotrimeric G-protein binding
  • many cysteine (and/or methionine) residues in intracellular domain
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12
Q

How does a GPCR respond when an agonist binds ?

A
  • it binds a heterotrimeric G-protein
  • GDP is kicked off and replaced by GTP
  • the alpha subunit (bound to GTP) dissociates from the beta-gamma subunits and activates intracullular effector –> biological response
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13
Q

How are heterotrimeric G-proteins “switched on” ?

A

By GPCRs which act as Guanine nt Exchange Factors (GEFs).

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14
Q

Once GTP bound, the alpha subunit of the G-protein binds to an effector.
What different molecules can this activate ?

A
  • adenylate cyclase
  • phospholipases
  • ion channels
  • Rho GEFs
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15
Q

How are G-proteins “switched off” ?

A

By G-protein Activated Proteins (GAPs) that hydrolyse GTP to GDP.

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16
Q

What does the beta-gamma complex do ?

A

It can also associated w/ and activate or inhibit effectors BUT IT HAS NO GTPase ACTIVITY !

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17
Q

What are the primary effectors of G-beta-gamma ?

A

Various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels + some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.

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18
Q

How many of each of the G-protein subunits have been cloned so far ?

A
  • 20 cloned α subunits
  • 13 γ subunits
  • 5 β subunits
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19
Q

What are the 4 classes of G-proteins which couple to different effectors ?

A
  • Gs –> Stimulates adenylate cyclase = cAMP signalling activated
  • Gi/o –> Gi inhibits adenylate cyclase = cAMP signalling inhibited
  • Go (via G-beta-gamma) –> inactivates Cas2+ and activates K+ channels
  • Gq –> Stimulates PLC = IP3 and DAG signalling
  • G12/13 –> Activates Rho to regulate the actin cytoskeleton
20
Q

How does Gα12/13 work ?

A

Gα12/13 binds to the RGS (Regulator of G-protein Signalling) domain of p115RhoGEF, LARG and PDZ-RhoGEF (Family F members).
These RGS proteins are Gα activated Rho GEFs.

21
Q

Do ligand/receptor pairs activate one specific effector ?

Are ligands specific to 1 effector ?

A

NO !
Different ligand/receptor pairs can act on the same effector.
One same ligand can act through different receptors to activate different effectors.

22
Q

What are the 2 major types of post-synaptic receptors ?

A

Ionotropic = ion channels

Metabotropic (referring to production of a metabolite or 2ary messenger) = GPCRs

23
Q

What are the characteristics of post-synaptic LG ion channels (e.g. nACh receptor) ?

A
  • v rapid to respond
  • Put on some NT = the channel opens, take off the NT = the channel closes
  • simple system
  • channel is part of the receptor
24
Q

What are the characteristics of post-synaptic GPCRs ?

A
  • Ion channel and receptor sites are in
    different locations
  • Uses intracellular messengers for communication between the NT binding site (receptor) to the ion channel = 2d messengers
  • Channel is NOT part of the receptor
  • Slow to respond as compared to LGICs
    (for GPCRs from tens of milliseconds to seconds)
  • Typically “extrasynaptic.”
  • Slow to shut down – requires not only removal of the NT but removal of downstream second messenger mediated effects (i.e. dephosphorylation)
25
Q

Where and how does ACh act ?

Why is this NT important ?

A
  • Mechanism of action: primarily direct, through binding to chemically gated ion channels (although some indirect via activation of MMRs (Mismatch Responses))
  • Locations: CNS (brain, sp chord) + PNS (NM jcts, neuroglandular jcts of sympathetic NS)
  • Importance: widespread in CNS and PNS, best knwon + most studied of the NTs
26
Q

Where and how does NA act ?

Why is this NT important ?

A
  • Mechanism of action: indirect, through G proteins + 2d messengers
  • Locations: CNS (Cerebral cortex, hypothalamus, brainstem, cerebellum, sp chord) + PNS (most NM jcts, neuroglandular jcts of sympathetic NS)
  • Importance: involved in attention and consciousness, control of body temperature + regulation of pituitary gland secretion
27
Q

Where and how does AD act ?

Why is this NT important ?

A
  • Mechanism of action: indirect, through G proteins + 2d messengers
  • Locations: CNS (Thalamus, hypothalamus, midbrain + sp chord)
  • Importance: general excitatory effect along autonomic pathways
28
Q

Where and how does 5-HT act ?

Why is this NT important ?

A
  • Mechanism of action: primarily indirect, through G proteins + 2d messengers
  • Locations: CNS (Hypothalamus, limbic syst, cerebellum, sp chord + retina)
  • Importance: crucial in emotional states, moods + body temperature; several illicit hallucinogenic drugs (e.g. Ecstacy) target 5-HT receptors
29
Q

Where and how does Glu act ?

Why is this NT important ?

A
  • Mechanism of action: indirect –> through G proteins + 2d messengers; direct –> opens Ca2+/Na+ channels
  • Locations: CNS (Cerebral cortex + brainstem)
  • Importance: crucial in memory and learning; most important excitation NT in the brain
30
Q

Where and how does GABA act ?

Why is this NT important ?

A
  • Mechanism of action: direct or indirect (G proteins) depending on type of receptor
  • Locations: CNS (Cerebral cortex, cerebellum, interneurons throughout brain + sp chord)
  • Importance: direct inhibitory effect –> opens Cl- channels; indrect effects –> opens K+ channels + blocks entry of Ca2+
31
Q

How can GPCRs amplify signalling ?

A

A few molecules can exert a big effect.

32
Q

What are potential targets for the 2d messengers activates by G proteins ?

A
  • channels in the membrane
  • metabolites in the cytoplasm
  • genes –> affect gene expression in
    the nucleus leading to long-lasting changes (e.g. memory?)
    Most of this done via kinases/phosphotases
33
Q

How can GPCRs exert multiple effects on a same target ?

A

Different GPCRs exert different effects on

the same enzyme.

34
Q

How abundant is dopamine in the human brain ?

A

It is found in relatively few neurons –> 1 million dopaminergic neurons out of the 10 billion neurons in cerebral cortex.

35
Q

Where are the 4 major dopaminergic tracts found ?

A

Nigrostriatal tract: fine tuning of movement;
Tuberoinfundibular tract: control of hormones
2 tracts within the Mesolimbocortical system: motivation + emotional behavior.

36
Q

Which dopamine receptors are excitatory ? - inhibitory?

A

D1-like receptors are Gs- coupled – D1A and D1B (D5)

D2-like receptors are Gi-coupled – D2, D3 and D4

37
Q

What is the consequence of excessive neurotransmission of DA ?

A

Schizophrenia = a clinical condition marked by seriously disordered thought

38
Q

What are antipsychotics ?
What therapeutic effect do they have ?
What are the potential undesirable effects ?

A
  • Antipsychotics/neuroleptics = a class of compounds with a high affinity for several subtypes of DA receptors
  • Blocking dopamine receptors in the limbic + cerebral cortex –> thought to be helpful in alleviating symptoms of schizophrenia.
  • Blocking D2 receptors in the basal ganglia + cerebellum –> responsible for undesirable side-effects: motor dysfunction, tremors, akinesia (a slowing of voluntary movements), spasticity and rigidity among others
39
Q

What are “atypical antipsychotics” ?

A
  • “Atypical antipsychotics” have fewer undesirable side effects –> have a lower affinity for D2 relative to D3/4 receptors
  • D3/4 receptor expression limited to neurons of the limib syst + cerebral cortex
40
Q

Why is 5-HT important ?

A

5-HT = a monoamine NT (synthesized from Trp), plays an important role in many behaviors including sleep, appetite, memory, sexual behavior, neuroendocrine function, and mood

41
Q

Where are the highest levels of 5-HT found in the brain ?

A

The dorsal and median raphe nuclear complex.

42
Q

How can we remove NT from the synaptic cleft ?

A
  • degredation e.g. AChesterase is on the surface of the
    post-synaptic membrane and in the synaptic cleft –> degrades ACh to Ch + Acetate
  • reuptake: reabsorb NT into the presynaptic element
  • diffusion out of the synaptic cleft
  • transporter proteins: active removal –> reduces the level of NT in the cleft faster than diffusion, constrains the effects of released NT to smaller areas, and allows at
    least part of the released chemical to be recycled
43
Q

What does the Lashachie Theorem state ?

A
  • At equilibrium, NT bound to the receptor is at the same
    concentration as NT not bound
  • Remove NT from the cleft and the NT on the receptors comes off (based on concentration gradients)
44
Q

How the the 5-HT transporter work ?

A
  • The serotonin transporter first binds 1 Na+, followed by 5-HT molecule, and then 1 Cl-.
  • The transporter then flips inside the cell, releasing 5-HT. 1 K+ binds, and the transporter flips back out, ready to receive another serotonin molecule.
45
Q

What is the driving force for the NRGetically unfavourable transport of 5-HT inside the cell ?

A

The Na+ influx down its electrochemical gradient. The Na+/K+ ATPase maintains the extracellular Na+ concentration as well as the intracellular K+ concentration.

46
Q

What is clinical depression ?

A

Clinical depression = one of the most common psychiatric disorders, with an incidence of about 4% and a life-time prevalence of 15-20%.
Despite significant research, the neurobiological dysfunctions of major depression remain elusive.

47
Q

What are SSRIs and why could they be potential therapeutic targets to treat depression ?

A

SSRIs = Selective Serotonin (5-HT) Reuptake Inhibitors
There is evidence that serotonergic pathways are the most closely related systems to mood disorders, especially depression, and thus SSRIs may lead to significant therapy.

NEUR1005 (31 decks)

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