.1) General principles of cell communication AND membrane receptors

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28 Terms

1

paracrine signalling

secreting cell secretes to nearby cells

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Autocrine signalling

Secreting cell is same as target cell

Hormone exits cell then enters cell

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Endocrine signalling

Secrete into circulation to target cell e.g. pancreas beta cells secreting insulin

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Juxtacrine signalling

Secreting cell targets adjacent cell

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Intracrine signalling

Hormone targets secreting cell and stays within cell

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Milestones in receptor biology

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Otto Loewi experiment

Evidence for receptors

  • Isolated two frog hearts and placed each of them in a chamber filled with saline

  • Connect them with a tube

  • Measure heart rate

  • Stimulate vagus nerve of one heart to slow down

  • After a delay the second heart gets stimulated

Hypothesis: electrical stimulation of the vagus nerve released a chemical into the fluid of chamber 1 that flowed into chamber 2. He called the chemical “Vagustoff” which we now know is the neurotransmitter ACh

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Henry dale

Isolated ACh from ergot (fungus)

Isolated ACh from human body

Proved with Loewi that ACh is a neurotransmitter

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ACh receptors

ACh receptors can have different effects

Can become ion channels

Agonist - compounds that produce the same effects as the neurotransmitter

Antagonist - blocks active site but has no response

<p>ACh receptors can have different effects</p><p>Can become ion channels</p><p>Agonist - compounds that produce the same effects as the neurotransmitter</p><p>Antagonist - blocks active site but has no response</p>
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Nicotinic AChR

Nicotinic AChR - two extracellular domains (binding sites) for ACh

Pentametric ion channel - 5 different subunits

transmembrane portion - alpha helices and intracellular domain

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muscle stripe

<p></p>
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Radioligand binding assay

incubate to allow binding

wash excess ligands

radioactivity proportional to number of receptors that have ligands bound

can measure affinity at a concentration of ligand

<p>incubate to allow binding</p><p>wash excess ligands</p><p>radioactivity proportional to number of receptors that have ligands bound</p><p>can measure affinity at a concentration of ligand</p>
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Affinity

How strongly a certain compound binds to a receptor

Affinity = 1 / KD

KD (equilibrium dissociation constant) - 50% of receptors occupied by ligand

Lower KD has a greater affinity

<p>How strongly a certain compound binds to a receptor</p><p>Affinity = 1 / KD</p><p>KD (equilibrium dissociation constant) - 50% of receptors occupied by ligand</p><p>Lower KD has a greater affinity </p>
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Types of receptors

Ligand gated ion channels (ionotropic)

  • milliseconds

  • Nicotinic ACh Receptors

G coupled protein receptors (metabotropic)

  • seconds

  • Muscarinic ACh receptors

  • largest family of membrane receptors

Kinase linked receptors

  • hours

  • Cytokine receptors

Nuclear receptors

  • hours

  • Oestrogen receptor

<p>Ligand gated ion channels (ionotropic)</p><ul><li><p>milliseconds</p></li><li><p>Nicotinic ACh Receptors</p></li></ul><p>G coupled protein receptors (metabotropic)</p><ul><li><p>seconds</p></li><li><p>Muscarinic ACh receptors</p></li><li><p>largest family of membrane receptors</p></li></ul><p>Kinase linked receptors</p><ul><li><p>hours</p></li><li><p>Cytokine receptors</p></li></ul><p>Nuclear receptors</p><ul><li><p>hours</p></li><li><p>Oestrogen receptor</p></li></ul>
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Kinase linked receptors

Summary: 

  1. GF (1st messenger) binds to receptor

  2. Causes dimerisation of receptor

  3. Tyrosine kinase regions are activated and become phosphorylated (6 x ATP)

  4. (Receptor tyrosine kinase) RTK is now fully activated

  5. Cellular proteins become activated which causes a cascade which initiates a cellular response

  • Speed: Slow

  • Example: Tyrosine kinase receptor

  • If these receptors are mutated, they cause cell proliferation and so are often implicated in various form of cancer.

<p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Summary:&nbsp;</span></p><ol><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">GF (1</span><sup>st</sup><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)"> messenger) binds to receptor</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Causes dimerisation of receptor</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Tyrosine kinase regions are activated and become phosphorylated (6 x ATP)</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">(Receptor tyrosine kinase) RTK is now fully activated</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Cellular proteins become activated which causes a cascade which initiates a cellular response</span></p></li></ol><ul><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Speed: Slow</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">Example: Tyrosine kinase receptor</span></p></li><li><p><span style="font-family: Calibri, sans-serif; color: rgb(0, 0, 0)">If these receptors are mutated, they cause cell proliferation and so are often implicated in various form of cancer.</span></p></li></ul>
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kinase

Phosphatase

Kinase - adds phosphate

Phosphatase - removes phosphate

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GPCRs

Mediate effects of many hormones and neurotransmitters

When G proteins are inactive they contain a nucleotide GDP

Alpha subunit contains enzymes which hydrolyse GTP to GDP to stop the reaction

GPCR typically have 7 alpha helixes and spans the plasma membrane 7 times

have alpha, beta and gamma subunits

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Types of G proteins

G alpha s - activates adenylyl cyclase (AC)

- opens calcium ion channels in some tissues

  • ATP —AC→ cAMP—cAMP phosphodiesterase → AMP

G alpha q - activates phospholipase C

G alpha i- inhibits AC

G alpha 12/13 - regulates small g proteins for cytoskeleton contraction

G beta gamma - regulate ion channels and enzymes like PLCb

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GPCR mechanism

agonist binds to receptors causing a conformational change allowing it to bind with the heterotrimetric G proteins

causes G protein to open and GTP binds to alpha subunit displacing GDP

G protein dissociated with receptor and alpha subunit separates from beta and gamma

subunits interact with other effectors initiating a biological response

alpha subunit hydrolyses GTP to GDP……

<p>agonist binds to receptors causing a conformational change allowing it to bind with the heterotrimetric G proteins</p><p>causes G protein to open and GTP binds to alpha subunit displacing GDP</p><p>G protein dissociated with receptor and alpha subunit separates from beta and gamma</p><p>subunits interact with other effectors initiating a biological response</p><p>alpha subunit hydrolyses GTP to GDP……</p>
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Phospholipase C (PLC)

PLC cleaves a membrane phospholipid, PIP2, to give two secondary messengers (IP3 and DAG)

DAG remains in cell membrane and attracts and activates protein kinase C

Calcium signalling

G protein dependent opening of ligand gated ion channels

Release of intracellular stores of calcium in ER mediated by release of IP3

Calcium acts as a secondary messenger activating calcium/calmodulin dependent protein kinase

<p>PLC cleaves a membrane phospholipid, PIP2, to give two secondary messengers (IP3 and DAG)</p><p>DAG remains in cell membrane and attracts and activates protein kinase C</p><p><u>Calcium signalling</u></p><p>G protein dependent opening of ligand gated ion channels</p><p>Release of intracellular stores of calcium in ER mediated by release of IP3</p><p>Calcium acts as a secondary messenger activating calcium/calmodulin dependent protein kinase</p>
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Example 1

Hormonal regulation of glycogen metabolism

Glucagon or Adrenaline binds to G alpha s

Activates AC

converts ATP to cAMP

Causes release of protein kinase A

Cascade of reactions converts glycogen to glucose

Same process inactivates glycogen synthase

cAMP phosphodiesterase keeps the reaction controlled by degrading cAMP to prevent the reaction from reoccurring, cAMP to AMP

<p>Glucagon or Adrenaline binds to G alpha s</p><p>Activates AC</p><p>converts ATP to cAMP</p><p>Causes release of protein kinase A</p><p>Cascade of reactions converts glycogen to glucose</p><p>Same process inactivates glycogen synthase</p><p></p><p>cAMP phosphodiesterase keeps the reaction controlled by degrading cAMP to prevent the reaction from reoccurring, cAMP to AMP</p>
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Example 2

Regulation of smooth muscle tone

Calcium bind with calmodulin and the complex stimulates myosin light chain kinase (MLCK)

Phosphorylates myosin light chain

Myosin light chain Phosphatase (MLCP) removes phosphate group

G alpha s induces muscle relaxation

<p>Calcium bind with calmodulin and the complex stimulates myosin light chain kinase (MLCK)</p><p>Phosphorylates myosin light chain</p><p>Myosin light chain Phosphatase (MLCP) removes phosphate group</p><p>G alpha s induces muscle relaxation</p>
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Example 3 - real life

TSH receptor signalling in the thyroid - Gαs

1) TSH (released via pituitary gland) binds to Gs-protein coupled receptors on the surface of thyroid cells leading to the production of cAMP which activates PKA 🡪 CREB activation (TF)

2) This leads to an increased replication of thyroid cells and it also induces the synthesis and release of thyroid hormones into the bloodstream.

<p>1) TSH (released via pituitary gland) binds to Gs-protein coupled receptors on the surface of thyroid cells leading to the production of cAMP which activates PKA 🡪 CREB activation (TF) </p><p>2) This leads to an increased replication of thyroid cells and it also induces the synthesis and release of thyroid hormones into the bloodstream.</p>
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cAMP/PKA pathway

alpha subunit interacts with AC.

AC converts ATP into cyclic AMP which binds to protein kinase activating Protein kinase A (PKA)

The activated PKA enters into the nucleus and helps activate CREB (transcription factor)

This induces a response which results in the secretion of hormones or cell replication.

PDE also degrades cAMP converting it into AMP to shut off signalling cascade.

<p>alpha subunit interacts with AC. </p><p>AC converts ATP into cyclic AMP which binds to protein kinase activating Protein kinase A (PKA)</p><p>The activated PKA enters into the nucleus and helps activate CREB (transcription factor)</p><p>This induces a response which results in the secretion of hormones or cell replication.</p><p>PDE also degrades cAMP converting it into AMP to shut off signalling cascade.</p>
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Effects of cAMP/PKA pathway in endocrine cells

Increase hormone secretion

Under prolonged stimulation - increased cell proliferation

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TSH receptor

Autonomous thyroid adenoma (ATA)

TSH is secreted by anterior pituitary

ATA - cause hyperthyroidism

- benign tumours caused by activating mutations in TSHR gene (somatic mutation)

TSH resistance - inactivating TSHR mutations

  • complete (very rare) - homozygous, severe congenital hypothyroidism

  • Partial (common) - heterozygous, mild hypothyroidism

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Cushing syndrome

Mutation in PKA C subunit

Adrenal tumour

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GPCR animation

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