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Principles of Neuronal Function and Dysfunction > G Protein Couple Receptors and Second Messengers > Flashcards

G Protein Couple Receptors and Second Messengers Flashcards

1
Q

What are the main types of second messenger ?

A
  • Cyclic nucleotides (e.g. cGMP, cAMP
  • Lipid messengers
  • Ions (e.g. calcium)
  • Endogenous gases (e.g. Nitric oxide)
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2
Q

What are the different types of cellular receptors?

A
  1. Intracellular Receptors
  2. Membrane Receptors
    - Ionotropic receptors
    - Catalytic receptors
    - G protein coupled receptors
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3
Q

What are some components of G protein signalling cascade ?

A
  • GPCR (discriminator)
  • G protein (transducer)
  • Effector (amplifier)
  • Secondary messenger
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4
Q

What are some examples of G protein coupled receptors and explain?

A
  1. Opioid receptors
    - Opium is produced from the opium poppy and contains over 20 alkaloids including morphine. Morphine manifestsIts action through the activation of opioid receptors
  2. Muscarinic cholinergic receptors
    - Muscarine was first isolated from the mushroom Amanita muscaria. Some of the toxic effects of this mushroom are caused by the action of muscarine on muscarinic receptors
  3. Cannabinoid receptors
    - Cannabis contains 61 different alkaloids. Cannabinoid receptors are present almost everywhere in the CNS2
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5
Q

What are the structures of GPCRs ?

A
  • Two-dimensional model of GPCRs

- X-ray structure of Rhodopsin

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6
Q

Classification of GPCRS: Family 1

A
  1. Catecholamines (adrenaline, noradrenaline, dopamine) - mediate so-called fight-or-flight response.
  2. Cytokines - are involved in the regulation of differentiation and survival of neural cells
  3. Glycoprotein hormones - are the most chemically complex family of the peptide hormones. Some of them are produced in the CNS.
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7
Q

Classification of GPCRS: Family 2

A

Secretine - is a peptide hormone consisting of27 amino acids. It is likely to be involved in learning and memory.

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8
Q

Classification of GPCRS: Family 3

A

GABA - is a major inhibitory neurotransmitter in the CNS.Glutamate is the most common excitatory neurotransmitter in the CNS.

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9
Q

Classification of GPCRS: Family 4

A

Pheromone receptors

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10
Q

Classification of GPCRS: Family 5

A

Cyclic AMP receptor–like receptors

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11
Q

Classification of GPCRS: Family 6

A

Frizzled receptors

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12
Q

Explain obligatory hetero-dimerization?

A

Heterodimerization of two protomers is required to form functional receptors

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13
Q

Explain non-obligatory hetero-dimerization? ?

A

Heterodimers are composed of the functional GPCR promoters

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14
Q

Explain homo-dimerization?

A

The interaction between GPCR monomers might serve as a mechanism for signal amplification

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15
Q

What is GABA ?

A

GABA (g-aminobutiric acid) is a major inhibitory neurotransmitter in the CNS

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16
Q

Explain the structure of functional GABAb receptors ?

A
  • The functional GABAb receptor is a constitutive dimer formed between GABAbR1 and GABAbR2
  • When expressed alone, the GABABR1 is retained in the endoplasmic reticulum (ER) because of the presence of an ER-retention sequence in the C-terminal tail
  • Co-expression of the GABABR2 results in the retention motif being masked and allows delivery of the dimer
17
Q

What are G proteins ?

A

G proteins are globular proteins found on the inside of the cell membrane. They have been called ‘G proteins’ because of their ability to bind either Guanosine diphosphate (GDP) or Guanosine triphosphate (GTP)

18
Q

Explain the receptor-dependent activation of G proteins ?

A
  1. The α subunit bound to GDP interacts with the βγ dimer to form G protein in its inactive resting state
  2. Binding of an agonist stabilises the active conformation of GPCRs. This uncovers previously masked G protein-binding sites
  3. When bound to a GPCR, the G protein undergoes important conformational changes. This provokes the dissociation of GDP from the α subunit
  4. GTP binding induces changes in the conformation within subunit. Activated α subunit dissociates from the receptor and the βγ dimer
  5. Free activated α subunit and βγ dimer can now modulate activities of many targets in the cell.
19
Q

Indirect actions of activated G proteins are mediated by?

A

Primary effectors

20
Q

Cellular responses caused by indirect actions are ?

A

Slower than those caused by the direct interaction between G protein subunits and ion channels

21
Q

What do activation of effector proteins lead to ?

A

Significant amplification of the signal

22
Q

Different types of α subunits interact in a highly specific manner with effector protein. Name them and what they do ?

A
  • αs stimulates Adenylyl cyclase
  • αi inhibits Adenylyl cyclase
  • αq activates Phospholipase C
  • α12 & α13 activate Rho
  • αt activates cGMP-phosphodiesterase
23
Q

What does Adenylate cyclase contain ?

A

Adenylate Cyclase contains two hydrophobic domains each consisting of 6 transmembrane segments separated by a large (40 kDa) cytoplasmic loop

24
Q

What does cAMP activate?

A

cAMP-dependent protein kinase (PKA)

25
Q

What does Phospholipase A2 do ?

A

It catalyses the release of Arachidonic Acid from cell membrane phospholipids

26
Q

What does Arachidonic acid pathway play a critical role in ?

A

In the initiation, maintenance, and modulation of neuroinflammation and oxidative stress

27
Q

What brain disorders are characterised by increased activities of brain phospholipase A2 is-forms?

A

Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, bipolar disorder and schizophrenia

28
Q

What is the process of Activated GPCR to Inactivated GPCR ? (seconds)

A

Desensitisation (receptor becomes refractory to continued stimuli)

29
Q

What is the process of Inactivated GPCR to Internalised GPCR ? (minutes)

A

Sequestration (removal of receptors from the cell membrane)

30
Q

What is the process of Internalised GPCR to Decrease in total amount of GPCR ? (hours)

A

Downregulation (decrease in total amount of receptors within a cell)

31
Q

Desensitisation of GPCRs depends on ?

A

Their phosphorylation by protein kinases

32
Q

Second messenger-dependent protein kinases (PKC, PKA) can phosphorylate Second messenger-dependent protein kinases (PKC, PKA) can phosphorylate ?

A

Both agonist-bound GPCRs (homologous desensitisation) and unliganded GPCRs (heterologous desensitisation)

33
Q

GPCR protein kinases (GRKs) phosphorylate ?

A

Mainly agonist-activated GPCRs

34
Q

Explain regulation of GPCRs trafficking in neurons - Acute stimulation?

A

The internalised receptors can be either recycledor sent to the lysosomes. The overall amount of receptors remains, however,roughly the same due to neosynthesis

35
Q

Explain regulation of GPCRs trafficking in neutrons - Chronic stimulation?

A

The majority of internalised receptors are targeted to the lysosomes. Recycling is limited and neosynthesis is suppressed. This results in downregulationof GPCRs

Principles of Neuronal Function and Dysfunction (15 decks)

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