Cell signalling

• Contact-dependent signalling requires direct contact between the signalling cell and recipient or target cell. Examples are gap junctions and through cell surface molecules
• Gap junctions are hexameric channels that allow the diffusion of small molecules between two connected cells. Usually molecules less than 1 kDa especially ions (Ca2+)
• • Atrial fibrillation is the most common cardiac arrhythmia
  • particularly common in older patients
  • a consequence is stagnant blood pooling in the atria promotes thrombosis and is a leading cause of embolic stroke
  • atrial tissue expresses Cx40 and Cx43
  • connexins are normally at the polar ends of myocytes in the intercalated disks
• In familial atrial fibrillation connexin trafficking defects - reduction in gap junctional conductance and altered expression of Cx40.
• Charcot-Marie-Tooth neuropathy affects peripheral nerves
• Charcot-Marie-Tooth neuropathy causes gait problems in infancy or later in childhood.
• The X-linked form of Charcot-Marie-Tooth is the second most common form. CMT1X is caused by >400 different mutations in the GJB1 gene that encodes the gap junction protein connexin32
• Charcot-Marie-Tooth

  • Cx32 forms gap junctions between layers of schwann cell myelin sheath
  • many Cx32 mutants that cause CMT1X fail to form functional channels
  • other mutants form functional channels with altered biophysical characteristics such as reduced pore diameter that may prevent diffusion of second messengers
  • in peripheral nerves decrease conduction velocity of action potentials leading to muscle atrophy
• • long QT syndrome is identified by abnormal QT interval prolongation on ECG
  • may arise from decrease in repolarising cardiac membrane currents and increase in depolarising cardiac currents late in cardiac cycle
  • delayed repolarisation due to reductions in rapidly or slowly activating delayed repolarising cardiac potassium current
  • prolonged depolarisation due to small persistent inward leak in cardiac sodium current
• mutations in heart Na+ and K+ channels can lead to cardiac channelopathy long QT syndrome. susceptibility to cardiac arrhythmias following a trigger e.g. exercise
• SCN5a gain of function

  • LQT3
• SCN5a loss of function

  • brugada syndrome
  • idiopathic ventricular fibrillation
  • progressive cardiac conduction disease
  • congenital sick sinus syndrome
• KCNQ1 loss of function

  • LQT1
• KCNQ1 gain of function

  • familial atrial fibrillation
  • short QT syndrome
• KCNH2 loss of function

  • LQT2
• KCNH2 gain of function

  • short QT syndrome
• most receptor tyrosine kinases activate Ras - a monomeric GTP-binding protein (GTPase)
• constitutively active - active regardless of whether it is bound to a stimulus
• mutated receptors can be targeted for treatment
• egfr - colorectal cancer
• erbb2 - breast cancer
• IN the absence of a ligand GPCR is inactive
• GPCRs bind to G proteins which are a trimeric protein a, B and y subunits
• G proteins bind GDP when the GPCR is inactive but bind GTP when active. Also causes trimeric protein to split and two signals
• G protein hydrolyses GTP to GDP to inactivate GPCR
• Cholera is characterised by severe water loss, vomiting and muscle cramps
• Cholera is caused by infection with Gram negative bacterium Vibrio cholera
• Cholera toxin binds to enterocytes (epithelial cells in GI tract) and toxin enters cell by endocytosis
• A subunit of cholera toxin stimulates fluid secretion by activating cyclic AMP formation
• Cholera A subunit activates Gsa

  • G protein in GTP bound form
  • stimulates adenylate cyclase
  • cAMP produced activates PKA
  • CFTR phosphorylated and activated
  • efflux of Cl- (plus Na+ and water)
• an example of decrease in production of G proteins is pseudohypoparathyroidism - genetic loss of G(s) protein a subunits results in no response to parathyroid hormone
• an example of decreased signal initiation is whooping pertussis - a bacterial toxin adds ADP-ribose to receptor-binding C-terminal tail of G(i) protein a subunits, causing reduced responsiveness of G proteins to receptor activation
• an example of increased signal initiation is essential hypertension - mutations in G protein B subunits
• Defective GPCR signalling mechanisms

  • decrease in production of G proteins
  • decreased signal initiation
  • increased signal initiation
  • defective signal termination
• GPCRs are highly targeted by the pharmaceutical industry