1 - Receptors/Signal Transduction Pathways

Receptor

• Binds a ligand (drug or endogenous molecule)

• Transduces that binding event into a biological response

Drug-cell communication process

1. Reception – drug binds receptor

2. Transduction – signal is converted inside the cell

3. Response – cell function changes

What does receptor type determine?

• Where communication occurs

• How fast the effect begins

• How long the effect lasts

List receptor types from fastest to slowest

ligand-gated ion channels, GPCRs, enzyme-linked receptors, intracellular receptors

Ligand-gated ion channel signal transduction steps

1. Reception: Ligand (e.g., acetylcholine, GABA) binds to the channel on the cell membrane

2. Transduction: Channel undergoes a conformational change → pore opens

3. Response: Rapid ion flow (Na⁺, K⁺, or Cl⁻) alters membrane potential

Examples of ion-gated channel receptors

-       Nicotinic acetylcholine receptor → Na⁺ influx → depolarization

-       GABA-A receptor → Cl⁻ influx → hyperpolarization

GPCR signal transduction

Signal Transduction Steps

1. Reception: Ligand binds GPCR on cell membrane

2. Transduction:

   • GDP → GTP exchange on G protein

   • Activated G protein regulates an effector enzyme

3. Response:

   • Second messengers activate kinases

   • Kinase cascades phosphorylate target proteins

Major GPCR pathways (Gs, Gi, Gq)

• Gs → β-adrenergic receptors → ↑ cAMP → PKA activation

• Gi → α₂-adrenergic receptors → ↓ cAMP

• Gq → M₁ (and M₃) receptors → ↑ IP₃, DAG, Ca²⁺ → PKC activation

Enzyme-linked receptor signal transduction steps

1. Reception: Ligand binds extracellular domain → receptor dimerization

2. Transduction:

   • Autophosphorylation of intracellular tyrosine residues

   • Recruitment of adaptor proteins (e.g., IRS)

   • Activation of signaling pathways (PI3K–Akt, MAPK)

3. Response:

   • Changes in metabolism

   • Protein synthesis

   • Gene expression changes

Intracellular receptor signal transduction steps

1. Reception: Ligand diffuses into the cell and binds intracellular receptor

2. Transduction:

   • Receptor dissociates from chaperones

   • Receptor dimerizes

   • Complex binds DNA hormone response elements (HREs)

3. Response:

   • Altered gene transcription

   • New protein synthesis

   • Long-term physiological effects

Receptor theory framework

• Receptors exist in two states:

  • Ri = inactive

  • Ra = active

• Even without a drug, some receptors have basal (constitutive) activity

• Drugs differ in how they shift the equilibrium between R and R*

Agonists

binds to the receptor and stabilizes the active (Ra) state, producing a biological response.

Partial agonist

activates the receptor but produces a lower maximal effect, even when all receptors are occupied

Inverse agonist

binds to the same receptor as an agonist but reduces receptor activity below basal levels (Ri).

Antagonists

binds to the receptor but has no intrinsic activity, blocking agonist effects without altering basal activity

Drug efficacy

the maximum effect (Emax) a drug can produce, determined by receptor activation

Drug potency

• the amount of drug needed to produce a given effect

• Often measured by EC₅₀ (dose producing 50% of max response)

T/F: activation of a receptor immediately causes a physiological effect

false

arrange in order of onset of action after receptor activation:

• enzyme-linked

• GPCR

• ligand-gated ion channel

• intracellular

1. ligand-gated ion channel

2. GPCR

3. enzyme-linked

4. intracellular

Tazarotene, a topical retinoid, binds an intracellular receptor. Should results be expected within a few minutes?

no

Drugs that bind intracellular receptors require changes in _______ to elicit a physiological effect

gene expression

An immediate physiological effect typically occurs with activation of which receptor?

ligand-gated ion channel

Where are ion channels, GPCRs, and enzyme-linked receptors located?

cell membrane

Drugs that bind an intracellular receptor go where after binding?

cell nucleus

On a dose-response curve, what is represented on the x-axis?

drug dose

On a dose-response curve, what is represented on the y-axis?

effect/response

List what receptors represent each line on the dose-response curve:

1. full agonist

2. partial agonist

3. antagonist

4. inverse agonist

T/F: GPCRs always require an agonist for activation

false

Which receptors are most accurately depicted by this graphic?

GPCRs, enzyme-linked receptors

A drug has a markedly delayed onset despite high receptor affinity. which receptor type does it most likely bind?

intracellular receptor

A drug has an immediate effect despite low receptor affinity. which receptor type does it most likely bind?

ion channel

Full, partial, and inverse agonists are terms commonly used to describe binding to which type of receptor?

GPCRs