Receptor Structure Flashcards
What are the four structurally distinct receptor families?
- Ligand-gated ion channels (LGICs)
- G-protein coupled receptors (GPCRs)
- Kinase-linked and related receptors
- Nuclear receptors
Please give an example for each of the four families.
LGICs - nAChR
GPCRs - mAChR
Kinase-linked - insulin receptor
Nuclear - oestrogen receptor
Describe the structure of LGICs.
LGICs are:
- multi-subunit (oligomeric) as either pentameric, tetrameric or trimeric
- transmembrane proteins
- contain an integrated ion channel
- are either excitatory (e.g. Na+ channel) or inhibitory (Cl- channel)
Distinguish between the excitatory and inhibitory LGICs
Excitatory <===> receptors for ACh, 5-HT, Glu and ATP
Inhibitory <===> Receptors for GABA and Gly
Distinguish between the pentameric, tetrameric and trimeric LGICs
Penta <===> nAChR, GABA(A)R, GlyR, 5-HT(3)R
Tetra <===> GluR
Trimeric <===> P2X
List some examples of neurotransmitter LGIC receptors.
ACh <===> nAChR 5-HT <==> 5-HT(3)R GABA <==> GABA(A)R Gly <==> GlyR Glu <==> GluR ATP <==> P2X
What are the subtypes and subunits of nAChR?
Subtypes: muscle, neuronal
Subunits:
muscle <==> alpha(1), beta(1), gamma, delta, epsilon
neuronal <==> alpha(2) - alpha(10), beta(2) - beta(4)
What are the subunits of GABA(A)R?
alpha(1) - alpha(6) beta(1) - beta(3) gamma(1) - gamma(3) delta epsilon theta pi rho(1) - rho(3)
What are the subtypes and subunits of GluR?
subtypes: AMPA, Kainate, NMDA
subunits:
AMPA <==> GluA1 - A4
Kainate <==> GluK1 - K5
NMDA <==> GluN1, N2A - 2D, N3A - 3B
What are the subunits of
5-HT(3)R?
5-HT(3)A - 5-HT(3)E
What are the subunits of
ATP (P2X) R?
P2X(1) - P2X(7)
Describe the structure and nAChR.
- expressed at the NMJ and within the CNS and PNS
- also expressed in high density in the electric organ of the marine ray ‘Torpedo’ (alpha(2)-beta-gamma-delta)
- three dimensional structure of Torpedo nAChR obtained through cryo-electron microscopy
- has two conformations: open and closed
State five subtypes of GPCRs.
- Neurotransmitters
- Neuropeptides
- Peptide hormones
- Glycoprotein hormones
- Odorants
What are G-proteins?
Heterotrimeric proteins composed of alpha, beta, and gamma subtypes that catalyze the interconversion of the GTP and GDP
Describe the structure of GPCRs.
- Extracellular N-terminus
- Intracellular C-terminus
- 7 alpha-helical transmembrane domains
- several GPCRs exist as dimers (either homo- or hetero-dimers)
Give an example for a GPCR that exists as a dimer
GABA(B)R1 fails to form a functional cell-surface receptor unless as a dimer with GABA(B)R2
What was the first GPCR structure determined?
Rhodopsin, a light-sensing protein involved in the visual system
What was the first ligand-binding GPCR structure determined?
Beta(2) - adrenoceptor structure determined in 2007.
Beta(2) - adrenoceptor coupled to a cytoplasmic heterotrimeric G-protein structure determined in 2011.
Describe how GPCRs mediate intracellular signalling.
- GPCRs mediate intracellular signalling via interaction with intracellular G-proteins.
- Activation of GPCRs leads to the release of GTP-bound alpha subunits
- These then diffuse away and activate various enzymes, such as adenylate cyclase and phospholipase C
- This modulate the synthesis of second messengers of cAMP and IP(3).
- G-proteins can also act by modulating the function of ion channels.
List the different subtypes of GPCRs and provide an example for each.
Muscarinic AChRs <==> mAChRM(1) - mAChRM(5)
Metabotropic GluRs <==> mGluR(1) - mGluR(7)
5-HT receptors <==> 5-HT(1)R, 5-HT(2)R, 5-HT(4)R - 5HT(7)R
(note that 5-HT(3)R is a LGIC)
GABA receptors <==> GABA(B)R1, GABA(B)R2
Dopamine receptors <==> D1A, D1B, D2 - D5
Adrenergic receptors <==> alpha(1), alpha(2)A - alpha(2)C, beta(1) - beta(3)
Describe the structure of Kinase-linked and related receptors.
N-terminus — Ligand binding domain — [single transmembrane domain] — intracellular catalytic domain — C-terminus
What form of substrates bind to Kinase-linked and related receptors? Provide some examples.
They act as receptors for a wide range of signalling molecules, all of which are peptides.
Examples include:
- peptide hormones (e.g. insulin)
- growth factors (e.g. epidermal growth factor (EGF))
- cytokines
How are Kinase-linked and related receptors sub-divided? Provide some examples.
Based on signalling / catalytic activity. For example:
- tyrosine kinase receptors
- tyrosine kinase-linked receptors
- serine/threonine kinase receptors
- guanylate cyclase receptors
What happens if a receptor lacks an intrinsic catalytic activity?
It typically binds to cytosolic kinases and activate them after receptor activation. A common mechanism of action is for ligand binding to cause receptor dimerisation.
In receptors with intrinsic tyrosine kinase activity, this can result in auto-phosphorylation of tyrosine residues, which in turn can lead to binding of a group of intracellular proteins called SH2-domain proteins.
Describe the structure and function of Nuclear (intracellular) receptors
N-terminus — DNA binding domain — Ligand-binding domain — C-terminus
Nuclear receptors are soluble receptors, rather than transmembrane receptors.
Nuclear receptors regulate gene transcription.
What is the effect of a ligand binding to a nuclear receptor?
Induces a conformational change which promotes dimerisation.
The dimeric, ligand-bound receptor is able to act as a transcription factor by binding to specific regions of genomic DNA, promoting binding of RNA polymerase and thereby leading to gene transcription (of genes linked to hormone-responsive elements).
State the time periods relating to the effect of each of the four receptor families.
LGICs <==> fast (milliseconds)
GPCRs <==> slower (seconds)
Kinase-linked <==> even slower (hours)
Nuclear <==> slow (hours, sometimes days)
