Part 3 · Chapter 3.1

Receptor Types

Cellular receptors fall into four major superfamilies by signalling mechanism: ligand- gated ion channels, G-protein-coupled receptors (GPCRs), enzyme-linked receptors (mainly RTKs), and intracellular (nuclear / cytosolic) receptors. Each uses a distinct mode of signal transduction with characteristic kinetics, amplification, and downstream cascades.

1. Four Superfamilies

Ligand-gated ion channels: nAChR, GABA_A, NMDA — fast (ms) Na⁺/K⁺/Ca²⁺ fluxes at synapses.
GPCRs (7-TM): muscarinic, adrenergic, opioid. ~800 human genes, 35% of approved drugs. 100 ms–s via heterotrimeric G proteins.
Enzyme-linked RTKs: EGFR, insulin, FGFR — ligand-induced dimerisation, autophosphorylation, SH2-adaptor recruitment.
Intracellular: steroid, thyroid, vitamin-D nuclear receptors — ligand-bound translocate to nucleus, regulate transcription over hours to days.

2. Ligand-Receptor Binding

Equilibrium binding follows mass action:

\[ [RL] \;=\; \frac{[R_{tot}]\,[L]}{K_d + [L]},\qquad K_d = \frac{k_{off}}{k_{on}} \]

EC₅₀ (ligand producing 50% response) equals K_d only without downstream amplification. Most receptor systems show EC₅₀ < K_ddue to “spare receptors” — full response from partial occupancy. Cooperative binding (Hill n > 1) sharpens dose-response curves and is typical of multi-subunit ion channels.

Simulation: Dose-Response

Python

script.py22 lines

import numpy as np, matplotlib
matplotlib.use('Agg')
import matplotlib.pyplot as plt

L = np.logspace(-12, -4, 300)
def hill(L, Kd, n=1, Emax=1): return Emax * L**n / (Kd**n + L**n)
classes = {'GPCR (muscarinic)':(1e-9,1.0,'#60a5fa'),'RTK (EGF)':(1e-10,1.0,'#fbbf24'),
           'Ion channel (nACh)':(5e-7,1.8,'#34d399'),'Nuclear (estrogen)':(1e-10,1.0,'#f472b6')}
fig, ax = plt.subplots(figsize=(11, 6), facecolor='#0a0f1e')
ax.set_facecolor('#111e2f'); ax.tick_params(colors='#bae6fd')
for s in ax.spines.values(): s.set_color('#334155')
for name,(Kd,n,col) in classes.items():
    ax.semilogx(L, hill(L,Kd,n), color=col, lw=2.5, label=f'{name}  Kd={Kd:.0e}  n={n}')
ax.set_xlabel('Ligand concentration (M)', color='#bae6fd')
ax.set_ylabel('Fractional response', color='#bae6fd')
ax.set_title('Dose-response across receptor classes', color='#67e8f9', fontweight='bold')
ax.grid(True, color='#334155', alpha=0.3)
ax.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')
plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0f1e')
print('GPCRs and RTKs: picomolar-nanomolar Kd typical')
print('Ligand-gated ion channels: micromolar, often cooperative (Hill n>1)')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. Agonists, Antagonists, Biased Ligands

Full agonists elicit maximum response; partial agonists remain submaximal even at saturation. Competitive antagonistsright-shift dose-response without altering E_max; non-competitive depress E_max. Biased ligands(Kenakin 2011) selectively engage one downstream pathway — e.g., G-protein vs. β-arrestin at a GPCR (TRV130 oliceridine at μ-opioid).

4. Desensitisation

Persistent agonist produces desensitisation: tachyphylaxis at nAChR (seconds), β-arrestin GPCR internalisation (minutes), RTK ubiquitination/lysosomal degradation (hours), nuclear-receptor transcriptional self-repression (days). Each timescale matches the physiological role of the signal.

Key References

• Alberts, B. et al. (2022). Molecular Biology of the Cell, 7th ed. Garland.

• Kenakin, T. (2011). “Functional selectivity and biased receptor signaling.” J. Pharmacol. Exp. Ther., 336, 296–302.

• Lefkowitz, R. J. (2007). “Seven transmembrane receptors.” Biochim. Biophys. Acta, 1768, 748–755.

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