Cellular receptors
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Cellular Receptors. Chapter 2. Binding of Drugs in/to Cells. Receptor = Drug “target” Membrane protein Enzyme Nucleic acid Most drugs bind receptors by weak, noncovalent forces (what are these?) May be reversed by pH change. Molecular Recognition  Specificity. Cellular specificity

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Cellular Receptors

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Cellular receptors

Cellular Receptors

Chapter 2


Binding of drugs in to cells

Binding of Drugs in/to Cells

  • Receptor = Drug “target”

    • Membrane protein

    • Enzyme

    • Nucleic acid

  • Most drugs bind receptors by weak, noncovalent forces (what are these?)

    • May be reversed by pH change


Molecular recognition specificity

Molecular Recognition  Specificity

  • Cellular specificity

    • Not all receptors in all cells, tissues

  • Receptors selectively bind partic ligands

    • Stereoselectivity

  • No drug completely specific


Ligand receptor interactions

Ligand/Receptor Interactions

  • Reversible, bimolecular reaction

    • D + R  DR  DR*  Response

    • Where R*=Receptor w/ conform’n change

    • Each will have rate constant

  • What does this remind you of??


Activating drugs agonists

Activating Drugs = Agonists

  • Drug/receptor binding

    •  conform’l change in receptor

    •  act’n “downstream” cell biochem pathway(s)

    •  tissue response

  • May bind at separate site on receptor

    • “Allosteric modulators”

    • Increases response to natural agonist


Some definitions

Some definitions

  • Affinity = tendency to bind receptor

    • Specificity

    • Association/dissociation constant

  • Efficacy = tendency to activate receptor

    • Full agonists elicit max response

    • Partial agonists elicit submaximal response


Antagonists bind receptors

Antagonists Bind Receptors…

  • BUT no activation occurs

    • No conform’l change in receptor, so no pathway response

  • May keep agonists from binding

    • Competitive

    • Book ex: curare blocks ACh from receptors of neuromuscular junction  inhib’n muscle depolarization  paralysis

  • Allosteric modulators may decrease natural agonist binding

  • Best antagonists have efficacy=0


Targets for drug action

Targets for Drug Action


Receptor superfamilies

Receptor Superfamilies

  • Ligand-gated ion channels

  • G protein-coupled receptors

  • Receptor tyrosine kinases

  • Nuclear hormone receptors


Ligand gated ion channels

Ligand-Gated Ion Channels

  • Brain, periph NS, excitable tissues (heart), neuromuscular junction

    • Nicotinic cholinergic receptors (neuromusc)

    • GABA receptors (brain)

    • Glutamate receptors (brain)

  •  change membr potential  fast synaptic transmission

  • Complex prot’s w/ multiple subunits


Book ex nicotinic receptor

Book Ex: Nicotinic Receptor

  • Number of subunits differs w/ tissue

    • Antagonists differ

    • Allows selective blockade neuromuscular junction

  • Multiple binding sites for Ach

    • Excitatory

    •  incr’d Na+/K+ permeability  incr’d depol’n  incr’d probability of action potential

  • Direct transduction (no biochem intermediates)


Cellular receptors

  • Allosteric modulators may increase/decrease transmitter response in ligand-gated channels

  • Ex: benzodiazepines

    • Antianxiety; sleep disorders

    • Bind GABA ligand-gated receptors

      • GABA inhibitory

    • Increases ability of GABA to open channels


G protein coupled receptors

G Protein Coupled Receptors

  • Single subunit

  • 7 helices span bilayer

  • Agonists may bind extracell N-terminal domain, or between helices

    • Few allosteric modulators known

  • Cytoplasmic loop couples to G protein


G proteins

G Proteins

  • Intermediary mol’s

  • Bind guanine nucleotides

  • Extrinsic (periph) prot’s at inside bilayer

    • Anchored to membr by fa chain

    • Shuttle between receptor, target prot’s

  • 3 subunits

    • GTPase activity by a


Cellular receptors

  • “Resting state” G prot – trimer w/ GDP occupying site on a subunit

  • Agonist binding receptor  conform’l change w/in cytoplasmic domain

  •  Receptor acquires high affinity for G prot  binding G prot to receptor

  • GTP replaces GDP

  • bg duplex dissoc’s from a-GTP

    • Diffuse along membr

    • Assoc w/ enzymes, ion channels  act’n or deact’n


Cellular receptors

  • Term’n activity w/ hydrol Pi from GTP w/ GTPase activity of a subunit

    • Trimer reunites

  • Single agonist binding can activate sev G-prot mol’s for sev prod’s/act’n results

    •  Amplification


Cellular receptors

  • Sev types G prot’s

    • Interact w/ diff receptors

    • Control diff effectors

      • Gs stim’s enz adenylate cyclase, PLC, others

      • Gi inhibits ad cyclase, PLC, others

    • Agonist specificity


Cellular responses

Cellular Responses

  • Amplification of signal through second messengers that activate kinases

    • cAMP

    • Phosphatidylinositol

  •  Control regulatory enz’s through covalent mod’n

  •  Large, varied cell responses

  • GPCRs also control

    • PLA  eicosanoid release

    • Ion channels  depol’n, transmitter release, contractility, etc.


Examples of gpcrs

Examples of GPCRs

  • Receptors for

    • ACh (muscarinic)

    • Neuropeptides

    • Ephinephrine

  • Muscle (3 types), liver, fat, epithelium, neurons


Receptor tyrosine kinases

Receptor Tyrosine Kinases

  • Single transmembr a helix

  • Large extracell domain

    • Agonist binding site

  • Large intracell domain

    • Some incorporate tyr kinase activity

    • Cytokine receptors assoc w/ cytosolic kinases

  • Agonist binding  act’n  dimerization

    • Monomeric form inactive


Cellular receptors

  • Dimerized receptors autophosphorylate tyr residues

  • Phosphorylated tyr attracts, binds SH-2 domain protein

    • Src Homology

    • Conserved seq recognizes phosphotyrosine on receptor

    • Various SH2-domain prot’s allow selectivity for spec receptors

    • Some are enzymes

      • Kinases

      • Phospholipases


Cellular receptors

  • Some SH-2 Domain prot’s are couplers for other cell prot’s w/ phosphorylated receptors

    • Phosphorylation cascades

    • Impt to cell division, diff’n

    • Ex: Ras/Raf/MAP kinase pathway

      • Impt to cancers


Cellular receptors

  • SH-2 Domain prot’s as couplers – cont’d

    • Ex: Jak-Stat Pathway

      • Impt for cytokines, growth hormone, interferons

      • Cytosolic kinase phosphorylates receptor dimer

        • Various Jak’s  specificity

      • SH-2 domain prot’s (Stat’s) attracted, phosph’d, dimerize

      •  Nucleus  gene expression


Nuclear hormone receptors

Nuclear Hormone Receptors

  • Intracellular

  • Most in nucleus

    • Some cytoplasmic

  • Three domains:

    • Agonist binding domain at C-terminal

    • Transcriptional control domain

    • DNA binding domain

      • Highly conserved

      • “Zinc fingers”


Cellular receptors

  • Ligands lipophilic

    • Traverse lipid bilayer

    • Examples:

      • Steroid hormones

      • Thyroid hormones

      • Vitamin D

      • Retinoic acid

        • Impt to embryo dev’t


Cellular receptors

  • Agonist binding to receptor  conform’l change

  •  Dimerization of receptors

  • Dimers recognize specific base seq’s on DNA near genes

    • Hormone responsive elements

    • ~200 bp upstream from genes

  • Binding DNA may activate or repress gene transcr’n

    • So “ligand-activated transcr’n factors”


Other targets of drugs

Other Targets of Drugs

  • Ion Channels

    • Ligands bind voltage (as well as ligand-gated) channels

      • Block channel

      • Affect gating

    • Activation GPCRs  phosph’n channel prot’s

      • Affect channel opening

      • Ex: opioids, b-adrenoreceptor agonists

    • Modulation intracell Ca+2, GTP, ATP

      • Channels may bind these mol’s

      • Ex: sulfonylureas act at ATP-gated K+ channels on pancreatic B-cells


Cellular receptors

  • Enzymes

    • Drug may be substrate analog

      • Competitive or irreversible inhibitor

    • False substrate

      • Appears as substrate, so taken up

      • Not useful as product

        • Ex: 5-FU blocks DNA synth

    • Prodrugs

      • Metabolism  active agent


Cellular receptors

  • Carrier molecules

    • Impt for transport across cell membr’s

    • Have recognition sites for natural mol

    • Examples:

      • Cocaine, antidepressants inhibit noradrenaline uptake

        • Amphetamine acts as false substrate

      • Loop diuretics affect Na+/K+/Cl- transporter in renal tubule

      • Cardiac glycosides inhibit Na+/K+ pump


Single agonist may have complex effects

Single Agonist May Have Complex Effects

  • Families of receptors for agonists

    • Ex: ACh receptors muscarinic, nicotinic

      • Further subtypes

  • Some receptors very specific

  • Some receptors bind similar ligands

    • Book ex: dopamine structurally sim to norepi, can stim b1-adrenergic receptors

  • Multiple receptor subtypes for one ligand can coexist in single cell


Regulation of receptors

Regulation of Receptors

  • Drugs, agonists decrease sensitivity of receptors to ligands

    • Fast: desensitization, tachyphylaxis

    • Gradual: tolerance, refractoriness, drug resistance

    • Usually w/ continuous exposure

  • Sensitivity can be increased

  • Sensitization, desensitization can occur by ligand to same ligand or another


Cellular receptors

  • May be due to

    • Change in receptors

      • Phosphorylation – inhibits ability to interact w/ G proteins

      • Slow conform’l change

    • Exhaustion of mediators

      • Ex: amphetamines relase amines from nerve terminals; when endogenous amines depleted, drug doesn’t work


Cellular receptors

  • Loss of receptors

    • Binding agonist to receptor  rapid migration complex to coated pits

      • Membr invaginations surrounded by clathrin

    • Form intracell vesicles

    • Receptor dissociates

      • Recycled to cell membr

    • Agonist degraded in lysosomes

      • OR May be released outside cell


Cellular receptors

  • Physiological adaptation

    • Receptor number not static

    • Hormones may incr, decr receptor number

      • Altered rate receptor synth

      • Slow

      • Upreg’n  supersensitivity

        • W/ antagonist

        • W/ inhib’n transmitter synth/release

      • Downreg’n  loss sensitivity

        • W/ prolonged exposure to agonists


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