RECEPTORS: A BRIEF INTRODUCTION

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RECEPTORS A BRIEF INTRODUCTION

• Alexa R. George, PharmD
• With significant contributions by
• Vicente Gonzalez, CRNA, MS

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Definitions

• Receptor- a specific protein that is the site for
  binding of a signaling molecule
• Can also be Enzymes, Na, K -ATPase pump,
  Nucleic acids
• Ligand- a compound that is specific for each
  receptor and activates the receptor, causing a
  biological response

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Definitions

• Agonist- a compound that binds to a receptor and
  causes activation and an effect can be natural or
  synthetic
• Full and Partial
• Inverse agonist- (tricky) a compound that binds
  to the receptor and produces the opposite of the
  expected effect

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Definitions

• Antagonist- compound that when bound to the
  receptor inactivates it and prevents the normal
  response, these are usually reversible
• Competitive competes with agonist for the same
  binding site, concentration of compound and
  affinity for receptor affect which one wins
• Noncompetitive binds to receptor at discrete
  site (different from agonist) and changes the
  maximal response

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Agonists vs Antagonists
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Definitions

• Non-polar molecules that are neutral in charge
• No net charge associated with them
• Polar molecules that do not have a net charge,
  however certain regions of the molecule have a
  partial negative and positive charge.
• Polar molecules are soluble in water (water
  itself is a polar molecule)

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Definitions

• Hydrophilic- water loving, these are molecules
  that are water soluble and not lipid soluble
• Hydrophobic- water hating, lipid but not water
  soluble
• Lipophilic- lipid loving, lipid soluble but not
  water soluble
• Lipophobic- lipid hating, water but not lipid
  soluble

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Types of bonds

• Covalent, ionic, hydrogen, hydrophobic, and van
  der Waals forces
• In order of decreasing bond strength
• Hydrogen binding, ionic and hyrophobic
  interactions play important role
• Forces contribute to structure of proteins
  (receptors) and interactions of drugs with
  receptors

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Cell structure

• Cell membrane, also called plasma membrane,
  separates the cell from the environment
• Composed of phospholipids arranged in a bi-layer
• Phospholipids are composed of a glycerol head and
  a fatty acid tail, the glycerol portion is
  hydrophilic and the fatty acid portion is
  hydrophobic

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Phospholipids
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Cell structure

• Plasma membranes have channels in them that allow
  proteins and other substances to enter the cell
  in a regulated fashion (Receptors)
• Ions do not penetrate plasma membranes and
  neither do large molecules.
• Small hydrophobic molecules can diffuse across
  plasma membranes (CO2, O2)

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4 Types of receptors

• Ion channel linked receptors
• Ligand-gated ion channels
• Voltage-gated ion channels
• G-protein coupled receptors
• Intrinsic enzyme linked receptors
• Tyrosine kinase
• Intracellular receptors
• Steroids

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Ligand-gated ion channel receptors

• These receptors open an ion channel when
  activated
• Ex. Nicotinic and glutamate receptors
• (excitatory),
• GABAA and glycine receptors
• (inhibitory)

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Voltage-gated channel receptors

• Open or close in response to changes in voltage
  in the cell
• Named by the ion they are permeable to
• Na, K, Ca2
• Play an important part in muscle contraction and
  propagation of action potentials
• Some are excitatory and some inhibitory
• Local anesthetics bind to the intracellular
  domain of the voltage-gated sodium channel

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G-protein coupled receptors

• Cause their effect through a protein in the G
  family class that in turn causes an effect in the
  cell by increasing or decreasing production of a
  protein
• Ex. Catecholamines
• Most numerous type of receptor
• Trans-membrane receptors
• G-proteins aß? subunits
• Influence activity of enzymes (adenylyl cyclase,
  phospholipase C) and ion channels

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G-protein coupled receptors

• Relay messages by acting on second messengers
  within the cell
• Second messengers cAMP, cGMP, calcium,
  calmodulin, inositol triphosphate (IP3)
• Second messenger actions are tissue specific

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Adrenergic receptors

• Associated with the sympathetic division of the
  Autonomic Nervous System (ANS)
• Located in CNS and peripheral tissues
• Characterized by the neuro-transmitters they
  respond to
• Epinephrine, norepinephrine
• Mostly tend to speed things up, fight or flight
  response

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Adrenergic receptors

• 3 major types
• Alpha (a)
• Beta (ß)
• Dopaminergic (D or DA)
• All G-protein coupled receptors

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Adrenergic receptors

• Alpha receptor subtypes
• a1 located in vascular smooth muscle, GU smooth
  muscle and liver
• Agonists increase IP3 and DAG
• a2 located in pancreatic islet cells (ß cells),
  platelets, nerve terminals, CNS, and vascular
  smooth muscle
• Activation decreases cAMP ? decreases NE
• IP3 Inositol triphosphate, DAG
  diacylglycerol
• cAMP cyclic adenosine monophosphate

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Adrenergic receptors

• Beta receptors subtypes
• ß1- located in the heart and kidney
  (juxtaglomerular cells)
• ß 2- located in smooth muscle of vascular,
  bronchial, GI and GU systems
• Activation of these receptors increases cAMP
• Most common uses
• ß1 antagonists (beta blockers)
• ß2 agonists

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Adrenergic receptors

• Dopamine receptor subtypes 5 in total
• D1 and D5 very similar in structure, however
  located in different areas of the brain and
  peripheral tissues, kidneys
• Activation increases cAMP
• Agonist effect ? vasodilation
• D2 , D3, D4 similar in structure, generally have
  the opposite effect as D1 and D5
• Activation decreases cAMP

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Cholinergic receptors

• Two main types
• Nicotinic (N) and Muscarinic (M)
• Each has subtypes
• Nicotinic ligand-gated ion channel receptors
• Muscarinic G-protein coupled type

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Cholinergic receptors

• 2 main Nicotinic receptor types
• Nm found in the post-synaptic skeletal
  neuro-muscular junction.
• Ligand-gated ion channel
• Nn found in the autonomic ganglia
  (post-ganglionic) and the adrenal medulla
• Activation by acetylcholine (agonist) opens Na
  and K depolarizing ion channel
• Action dependent on ion

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Cholinergic receptors

• Muscarinic receptors
• M1 present in CNS, autonomic ganglia, glands
  (salivary and gastric), enteric (GI) nerves
• Activation initiates IP3, DAG mechanism
• M2 present in CNS, heart, smooth muscle and
  autonomic nerve terminals
• Inhibition of cAMP and activation of K channel
• M3 present in CNS, abundant in smooth muscle
  and glands.
• Activation same as M1

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Cholinergic receptors

• M4 present in CNS, specially in the forebrain
• Inhibition of cAMP.
• M5 present in low levels in CNS, mainly
  associated with Dopamine neurons
• IP3, DAG mechanism (same as M1)

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GABA receptors

• Two main types
• GABAA found primarily in the CNS, nearly all of
  the CNS neurons respond to GABA
• About 20 use it as their main neurotransmitter
• Chloride channel receptor
• GABAB found mainly in peripheral tissues and
  sparsely in the CNS
• Both types have an inhibitory effect and are
  ligand-gated ion receptors

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GABA receptors

• GABA receptors A and B are similar, but do not
  react the same way
• GABAA receptors are target sites of barbiturates
  and benzodiazepines
• No effect on GABAB
• GABAB is the target site for baclofen, an
  antispasmodic agent
• Net result in activation of both types is
  post-synaptic inhibition by means of Cl- channel
  activation ? CNS depression

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Serotonin (5-HT) family

• Serotonin receptors found throughout the body
• CNS, periphery, GI tract
• All G-protein coupled receptors, except 5-HT3
  which is a ligand-gated ion channel
• Directly coupled to fast Na and K ion channels
• Management of drug-induced nausea/vomiting
• Ex. Zofran (Ondansetron) antagonist
• Vast majority of psychoactive drugs work on these
  receptors by modulating serotonin release, uptake

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Opioid receptors

• Mu (various subtypes)
• Kappa
• Delta
• All are G-protein-coupled receptors

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Opioid receptors

• Mu receptors have different subtypes, at this
  time the significance is not well understood
• Responsible for analgesia in the spinal and
  supraspinal areas, specifically the substantia
  gelatinosa in the posterior horn of the spinal
  cord
• Also in the brain in areas that are associated
  with pain interpretation
• Mu receptor
• Activation causes respiratory depression,
  decreased GI motility

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Opioid receptors

• Kappa receptors
• Located in the same area as the Mu receptors
• Activation does not cause respiratory depression,
  but causes decreased GI motility
• Can cause dysphoria

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Opioid receptors

• Delta receptors
• Responsible for supraspinal and spinal analgesia
• Activation causes modulation of hormone and
  neurotransmitter release

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Conclusion

• All drugs work by altering the proteins produced
  by cells.
• They can enhance, inhibit or facilitate receptors
  to carry out their normal functions.
• The same cascade can have different effects
  depending on the cell type being stimulated.
• It is important as a practitioner to be familiar
  with how a drug works at the receptor level. This
  will enhance your learning and your ability to
  understand a new drug.