133 Endocrine Signaling

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13-3 Endocrine Signaling / Signal Transduction
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• Review of Topic 13-2
• The Insulin Receptor Cascades

3

• Review of Topic 13-2
• The Leptin Receptor Cascades

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Cell Signaling

• The b-adrenoceptor Cascades
• Binding of a small messenger molecule
• Epinephrine/norepinephrine
• Interaction with the receptor causes a
  conformational change
• Activates G-protein binding sites in C-terminal
  domain
• G-protein interacts with another integral
  membrane protein (enzyme) adenylyl cyclase
• Downstream effects via cyclic-AMP

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Cell Signaling

• The b-adrenoceptor Cascades

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Cell Signaling

• The b-adrenoceptor Cascades

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Cell Signaling

• The b-adrenoceptor Cascades
• Mechanism of G-protein signaling
• Cyclic AMP an important messenger for a number of
  hormone axes
• GTP essential for activation of the enzyme which
  generates cyclic AMP adenylyl cyclase

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Cell Signaling

• The b-adrenoceptor Cascades
• Mechanism of G-protein signaling

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Cell Signaling

• The b-adrenoceptor Cascades
• G-protein structure
• Three subunits a, b, g
• Heterotrimeric G-proteins
• a subunit binds guanine nucleotides regulatory
• When inactivated a is bound to GDP and the b and
  g subunits
• a and g subunits also attached to membrane via
  lipid moieties

10
Cell Signaling

• The b-adrenoceptor Cascades
• G-protein function
• Hormone binding induces a conformational change
  in the receptor
• C-terminal domain of receptor interacts with
  G-protein
• Release of bound GDP
• Exchange for GTP
• Activated a subunit dissociates
• a subunit activates adenylyl cyclase

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Cell Signaling

• The b-adrenoceptor Cascades
• G-protein function

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Cell Signaling

• G-protein diversity
• 20 different a subunits
• 6 b subunits
• 12 g subunits
• Different G-proteins associate with different
  receptors (c-terminal domain specificity)
• Specific intracellular targets
• b-adrenoceptor-linked G-protein Gs
• Stimulates adenylyl cyclase
• Other G-proteins inhibit adenylyl cyclase - Gi

13
Cell Signaling

• The b-adrenoceptor Cascades
• Cyclic AMP pathway
• Formed from ATP via adenylyl cyclase action
• Degraded to AMP by phosphodiesterase

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Cell Signaling

• The b-adrenoceptor Cascades
• Cyclic AMP pathway
• Most effects of cAMP mediated via protein kinase
  A (PKA)
• cAMP binds to regulatory subunits of PKA
• Regulatory and catalytic subunits dissociate
• Catalytic subunits activated
• Phosphorylate serine residues on target proteins
• Good example of signal amplification

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Cell Signaling

• The b-adrenoceptor Cascades
• Cyclic AMP pathway
• Activation of protein kinase A

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Cell Signaling

• The b-adrenoceptor Cascades
• Cyclic AMP pathway
• Many cases activation of transcription of
  target genes containing cAMP response element
  (CRE)
• Signal carried by catalytic subunit of PKA
• Phosphorylates transcription factor CRE-binding
  protein (CREB) - dimerises
• Activation of cAMP-inducible genes

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Cell Signaling

• The b-adrenoceptor Cascades
• Cyclic AMP pathway

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Cell Signaling

• Cyclic AMP pathway
• Important in proliferation, differentiation of
  many cell types
• Protein kinases
• Protein kinase A
• Not independent action
• Protein phosphorylation reversed by phosphatases
• Terminate responses following receptor activation
  of protein kinases

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Cell Signaling

• Protein kinases
• Protein kinase A
• Level of phosphorylation of substrates finely
  controlled by balance of actions of the kinase
  and phosphatases

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Cell Signaling

• The Insulin Receptor Cascades Interaction with
  the Leptin Pathway