General Mechanisms of Hormone Action

1
General Mechanisms of Hormone Action

• Hormone 1st messenger
• Hormone binds to receptor on target cell
• Receptors can be in membrane, cytosol, and/or
  nucleus
• Most hormones have unique receptors
• Some hormones have multiple receptor subtypes

2
Second messengers

• Hormones with transmembrane receptors activate
  2nd messenger systems
• Figure 2.1

3
Plasma membrane receptors

• Used by most hormones (exceptions steroids,
  thyroid hormones)
• H binding causes conformational change in
  receptor gt activation
• Intracellular tail activates cascade of enzymes

4
Plasma membrane receptors

• Kinases phosphorylate cell-specific proteins
• Secretory proteins
• Transcription factors
• Receptor number is in constant state of flux

5
Four classes of membrane receptors

• Receptors that are enzymes
• Receptors that are channels
• Receptors that are coupled to G proteins
• Receptors with unknown signal transduction
  mechanisms

6
G proteins

• Transducers
• Couple to membrane-bound receptors
• 3 subunits (heterotrimers)
• Alpha (activated by binding of GTP)
• Beta
• Gamma
• Alpha uncouples upon activation gt activates
  effector enzyme

7
G proteins, contd.

• Different G proteins target different effector
  systems
• Gs gt adenylate cyclase
• Go gt phospholipase C
• Gi gt phosphodiesterase
• Go, Gi gt ion channels

8
cAMP pathway

• Adenylate cyclase activated by Ga subunit
• Converts ATP to cAMP
• Combines with cAMP-dep. kinase (PKA)
• PKA has 4 subunits
• 2 regulatory
• 2 catalytic

9
cAMP pathway

• cAMP binds with reg. subunit
• Cat. subunit is released to act as kinase
• May activate cascade of enzymes
• Amplification
• Phosphodiesterase inactivates cAMP
• Phosphoprotein phosphatases dephosphorylate
  target proteins

10
Genomic actions of cAMP

• Many effects of cAMP are nearly immediate
• Genomic actions are slower, longer-lasting
• Mediated by CREB
• CREB activ. by PKA
• Binds to CRE of specific genes to cause
  cell-specific mRNA expression

11
Guanylate cyclase (gc) / cGMP

• gc activated by Ga subunit
• gc converts GTP to cGMP
• cGMP binds to regulatory subunits of
  cyclic-nucleotide dependent kinase (e.g. protein
  kinase G)
• Catalytic subunits activate other kinases, etc.

12
IP3 / Diacylglycerol (DAG) Pathway

• Gao activates phospholipase C (PLC)
• Hydrolyzes membrane phospholipid to form
• Inositol triphosphate (IP3)
• Diacylglycerol (DAG)
• IP3 binds to its receptor on endoplasmic
  reticulum gt Ca2 released
• DAG activates PKC gt phosphorylates target
  proteins

13
Eicosanoids

• Phospholipase A2 alters membrane phospholipid gt
  arachidonic acid
• Prostaglandins, leukotrienes, prostacyclins,
  thromboxanes
• Activate cyclases to increase cyclic nucleotide
  formation (e.g., cAMP)

14
Other GPCR facts.

• Kinases utilized by G protein-coupled receptors
  typically phosphorylate serine/threonine residues
• Physiological consequences of genetic mutations
  in Gsa
• McCune-Albright Syndrome
• Precocious puberty
• Hyperpigmentation of skin

15
Tyrosine kinase receptors

• Intracellular domain has tyrosine kinase activity
  or recruits tyrosine kinases upon hormone binding
• Growth factor receptors typically have intrinsic
  tk activity
• Examples insulin, EGF, FGF, IGFs

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Insulin receptor

• receptors exist as dimers (not true for EGF, FGF)
• alpha and beta subunits
• Occupancy gt autophosphorylation of tails
• Docking and phosphorylation of IRS
• IRS gtgtgt mitogen-activated protein kinase (MAPK)
• IRS gt PI 3 kinase gt glucose transporter
  translocation
• Also MAPK activation of PLA2

17
Defects in insulin pathways

• Type A insulin resistance can involve mutations
  in cytosolic domain of receptor
• Majority of Type A patients have normal insulin
  receptors

18
JAK / STAT pathway

• prolactin, leptin, growth hormone receptors
• ligand binds to receptors dimerization
• JAK proteins recruited (tyrosine kinases)
• JAKs phosphorylate STATs
• STATs dimerize, enter nucleus and bind DNA

19
GH resistance syndromes

• Many involve mutations in GH receptor genes
• Laron syndrome
• Low circulating IGF
• Unresponsive to bioactive GH
• Reduced GH binding
• Inefficient dimerization