Chemical messengers

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Chemical messengers

• Al Mina, M.D.
• Erskine College

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• Presentation adapted from text materials from
  Vanders Human Physiology, 11th edition,
  Widmaier, Raff, and Strang

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Messaging sequence

• Messengerligand
• Receptor has binding site for ligand
• Binding leads to response (signal transduction)

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Receptors

• Usually transmembrane proteins
• Very specific regarding binding to messenger

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Key terms

• Many factors involved in determining interaction
  between ligand and receptor

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Specificity

• Receptors ability to bind to single or very
  limited type of ligand

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Saturation

• How many receptor sites are bound by messengers.
  Higher saturationhigher activity.

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Affinity

• How strongly does receptor bind to ligand

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Competition

• How effectively other similar compounds may be
  able to bind to same receptor

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Agonist

• Competes with normal chemical messenger but
  triggers the response.

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Antagonist

• Competes with ligand, but does not trigger
  response blocks the signal transduction.

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Downregulation

• Decrease in number of receptors
• Typically in response to high concentration of
  messenger

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Upregulation

• Increase in receptors

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Medications are all about receptors

• Huge amount of pharmautical industry research
  deals with these concepts

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Signal transduction pathways

• Binding of ligand leads to conformational change
  (receptor activation)
• Signal transduction pathway is activated, leading
  to cell response

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Lipid soluble messengers

• Able to penetrate membranes
• Receptors usually in nucleus
• Binding leads to gene transcription, protein
  synthesis (or possibly inhibiton of transcription)

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Water soluble messengers

• Bind at cell membrane
• Neurotransmitters, hormones, paracrine/autocrine
  agents (first messengers)
• Receptor activation may yield second messenger
  inside cell, which enacts response.

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Protein kinases

• Phosphorylates other proteins using ATP
• Intermediate step to response

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Pathways

• Receptor as ion channel
• Activated by ligand, conformational change opens
  ion channel (ligand gated ion channel)
• Ions move by diffusion

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Receptors which act as enzymes

• Receptor has protein kinase activity
• Transfers phosphate group to other proteins
• Creates cascade of events which leads to desired
  response

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Interaction with cytoplasmic kinases

• Similar to previous type except receptor does not
  directly have enzyme (kinase) activity.
• Associates with group of proteins (JAK kinases)

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Coupling with protein complexes

• G proteins complex with 3 subunits (alpha,
  beta, gamma)
• Associated with receptor
• Binding of messenger causes alpha unit to
  separate, then bind and activate second membrane
  protein
• G protein coupled receptors most common

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Second messengers
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cAMP

• Specific second messenger for G protein pathway
• G protein activates adenylyl cylcase
• Converts ATP to cAMP (cyclic adenosine
  monophosphate)
• cAMP activates protein kinase A leading to cell
  response.

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Why is this important?

• Illustrates signal amplification
• One adenylyl cyclase can activate many molecules
  of cAMP,
• each cAMP continues to activate protein kinases
  until broken down.
• One messenger can lead to potentially millions of
  product molecules.

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cAMP versatility

• Protein kinase activated by cAMP is surprisingly
  versatile
• Able to phosphorylate many different compounds
• Therefore cAMP is widely prevalent throughout
  many systems

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Phospholipase C

• G protein activated phospholipase C which
  catalyzes creation of two second messengers from
  breakdown of PIP2
• Diacylglycerol (DAG) and inositol triphosphate
  (IP3).
• DAG activates protein kinase C
• IP3 attaches to receptors on ER which activate
  calcium channels

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Calcium

• Important second messenger
• Normally has very low intracellular concentration
  (active transport)
• Concentration can increase in a variety of ways

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Calcium

• Plasma membrane calcium channels
• Endoplasmic reticulum
• Inhibit active transport
• Voltage gated channels (electrical stimulus)

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Calcium function

• Binds to and activates many cytosolic proteins
• Calmodulin most important

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Arachadonic acid

• Leads to formation of eicosanoids
• Initiated by first messenger activating
  phospholipase A2, which splits arachadonic acid
  off of a phospholipid
• Can then travel down one of two pathways

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Cycloogygenase

• Leads to prostaglandins (vascular and
  inflammatory action)
• Thromboxanes blood clotting, vascular

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Lipoxygenase

• Leukotrienes allergic, inflammatory response
  (respiratory)
• All eicosanoids are usually released and act
  locally (paracrine/autocrine agents)

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• Arachadonic acid considered second messenger, but
  it is also a substrate

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Blocking AA pathway