L2 - Cell signalling by lipophilic molecules

• Types of Surface Receptors (water soluble):

  • Ion channel
  • Change membrane expression
  • & other things
  • G-protein coupled receptors
  • Alter protein activity
  • & other things
  • Cytokine receptors
  • Regulate many cellular events
  • & other things
• Intracellular Receptors (lipophilic):

  • Steroid receptors
  • Alter gene expression & other things
  • Is lipophilic = lipid soluble
  • Different steroid hormones in body
  • Receptor inside cell → directed to nucleus
  • Effect what cell does by 2 things
  • 1) change protein cell is making or
  • 2) activity of proteins already has
  • Acts as transcription factor turns genes on & off
• What are steroids?

  • Molecules chemical based on modifications of cholesterol
  • Many different versions of steroid molecules but all based off of this - cholesterol
  • Is a complicated molecule
• Where Steroids are produced:

  • Look similar but have different actions
  • Adrenal cortex
  • Cortisol in response to stress
  • From adrenal glands
  • Aldosterone in response to a fall in BP
  • Gonads (sex hormones )
  • Female - progesterone, estradiol (types of oestrogen)
  • Male - testosterone, dihydrotesterone
  • Exist in both sexes, have different actions due to concentration of hormones in body
  • Neurosteroids
  • Produced by neurons & glial cells (from 1 neuron to another)
  • Based on the steroid pregnenolone
  • Multiple actions only within the brain
• Differences are little between hormones but receptors can tell the difference
• How Steroids act:

  • Wide range of actions
  • Depending on the steroid
  • But common theme dictated by their physiochemical property of being insoluble in water (hydrophobic) but soluble in lipid (lipophilic)
  • All essentially largely insoluble, but not completely insoluble
• Lipophilic hormones:

  • Can’t be stored therefore synthesised when needed
  • Cell can’t hold it as it’s lipid soluble - diffuse thru membrane
  • Needs a carrier protein that binds to it, so can exist in water environment comfortably
  • Enter blood & travel around body
  • Cross the membrane of the target cell & act on the intracellular receptors
• Stress cause the release of both adrenaline & cortisol from the adrenal gland

  • The increase in cortisol concentration in the blood is slower than that of adrenaline
  • But it remains elevated for longer
  • & its effects on target tissues are more prolonged
• Stress response:

  • Brain detects stress, results in pituitary gland releasing hormone ACTH, has 1 job go to adrenal cell to make cortisol
  • Releasing cortisol is a slow process & got to tell adrenal to make some (as is made & released)
  • Some stresses need an immediate response eg for something dangerous
  • So have another system, = systemic NS works w/ adrenaline (from adrenal glands), trigger fast response
  • Increase energy production, increase BP, tunnel vision, increase HR, slow digestive system
• Mechanism of cortisol release - cortisol production triggered by ACTH, which acts on receptors:

  • Adrenal cortical cells activated by ACTH via MC2 receptor
  • Activates a G-protein coupled receptor
  • Increases in cAMP
  • Stimulates protein kinase A (PKA)
  • PKA activates transcription factors (signals that go to a gene)
  • Increases expression of cortisol synthesising enzymes
  • More cortisol released into the blood
  • Lots of other stuff going on as well
  • Cortisol not made by 1 enzyme, multistep process (complicated)
• Steroids & its carrier protein:

  • Require a carrier protein in the blood
  • Most of the hormone is bound - ~ 1 % of it is free
  • Free & bound cortisol are in equilibrium (balance point)
  • Dynamic equilibrium (binds & unbinds, not fixed)
  • The free part enters the cell, shifts equilibrium so little bit more steroid is free
  • Only the free hormone is physiologically active
  • & therefore only thing important for physiology + to measure
  • Can be altered by disease or drugs
  • Important to distinguish free & bound hormone in clinical tests
• Steroid binding to its receptor:

  • Free steroid crosses into the target cell
  • Binds to its intracellular receptor
  • Turns genes on or off (most critical thing for a cell)
  • An inhibitory regulator dissociates
  • Heat shock proteins, stop receptors working, dissociated with steroid bound making it active
  • So work when wanted, time & place
  • Genes that will be turned on or off by steroids, that can alter transcription
  • Regulates mRNA transcription from those genes
• Steroids may also signal in other ways (in addition to classical role):

  • The classical pathway
  • Regulates gene transcription
  • Interaction w/ other transcription factors
  • On really important gene, so give it more messages
  • Need co-regulators (from other pathway)
  • Must have all of them (messages) to do stuff
  • Steroid-receptor complex having non-transcriptional roles
  • Can act on other things in cell
  • Can happen quickly compared to gene transcription
  • Steroids signalling via cell surface receptors
  • Certain steroids, oestrogen’s