Receptors, Receptor Potentials & Sensory Physiology

Intercellular Communication – Modes & Messengers

• Direct communication
  • Gap junctions (cytoplasmic bridges)
  • Direct linkage of complementary cell-surface markers
• Indirect chemical communication (extracellular messengers)
  • Paracrine secretion – local diffusion to neighbouring cells
  • Autocrine secretion – messenger acts back on the same cell that released it
  • Neurotransmitter secretion – release from axon terminal into synapse → local target (e.g. skeletal muscle)
  • Hormonal (endocrine) secretion – hormone enters blood → distant targets possessing specific receptors
  • Neurohormone secretion – neuron releases chemical into blood → distant receptor-bearing cells

Ligands & Receptors – Core Definitions

• Ligand: any endogenous or exogenous substance that binds to a receptor (NTs, hormones, histamine, antibodies, drugs)
• Physiological receptor
  • Macromolecule that specifically recognizes 1⁺ ligands
  • Functions as a signal discriminator in transduction pathways
• Multiplicity: a single ligand may bind several receptor types or sub-types (diverse actions)

Grand Classification of Receptors

• A. Cell-specific receptors
  • Membrane (surface) receptors – water-soluble ligands
  • Ligand-gated ion channels ★
  • G-protein-coupled receptors (GPCRs) ★
  • Tyrosine-kinase, serine-kinase, cytokine receptors, etc.
  • Intracellular receptors – lipophilic ligands
  • Cytoplasmic receptors (e.g. steroid hormones)
  • Nuclear receptors (e.g. thyroid hormone)
• B. Sensory receptors
  • Modified ending of an afferent neuron (e.g. Pacinian corpuscle)
  • Separate receptor cell synapsing onto an afferent ending (e.g. rods & cones → bipolar → ganglion)

Cell-Specific Receptors – Details

1. Membrane / Surface Receptors

Ligand-gated Ion Channels (Ionotropic)

• Receptor is the channel; opens within 10^{-4} \text{ s}
• Selective for \text{Na}^+, \text{K}^+, \text{Ca}^{2+}, \text{Cl}^- etc.
• Typical ligands: acetylcholine (Na⁺), GABA (Cl⁻)
• Can be modulated by G-proteins & phosphorylation cascades

G-Protein-Coupled Receptors (GPCRs)

• 7-TM receptor coupled to heterotrimeric G-protein (α,β,γ)
• Ligand binding → GDP–GTP exchange on G_\alpha → dissociation → effector enzyme (AC, PLC) activation → second messengers (cAMP, IP₃, DAG, Ca²⁺)
• Massive signal amplification
• Therapeutic focus: many drugs target GPCRs

Tyrosine-Kinase Receptors (RTKs)

• Ligand binding → receptor dimerisation → autophosphorylation of Tyr residues → docking of signalling proteins → multiple responses (growth, metabolism)

2. Intracellular Receptors

Cytoplasmic (Steroid) Receptors

• Lipid-soluble hormone diffuses → binds cytosolic receptor → hormone–receptor complex translocates to nucleus → binds hormone-response elements → gene transcription/translation

Nuclear (Thyroid) Receptors

• Hormone diffuses directly into nucleus → binds DNA-bound receptor → alters transcription
• Slower onset, longer duration due to transcriptional mechanism

Sensory Receptors – Architecture & Types

• Why needed?
  • Allow organisms to adapt to external environment, generate reflexes, & enable neurological examination
• Modalities
  • Mechanoreceptors (stretch, pressure, vibration)
  • Thermoreceptors (heat, cold)
  • Electromagnetic (rods & cones – light)
  • Chemoreceptors (taste, smell, \text{O}2, \text{CO}2, pH)
  • Nociceptors (pain)
  • Osmoreceptors (ECF osmolarity)

Skin Mechanoreceptors & Adaptation Rates

Signal Transduction – From Stimulus to AP

1. External stimulus deforms receptor / binds channel → opens non-voltage-gated \text{Na}^+ channels
2. Receptor potential (graded depolarisation)
   • Amplitude ∝ stimulus strength
   • Duration ∝ stimulus duration
3. If depolarisation reaches threshold V_{th} at first node of Ranvier → voltage-gated \text{Na}^+ channels open
4. Action potential propagates along afferent fibre (all-or-none)

Two Structural Variants

a) Specialized Ending of Afferent Neuron

Stimulus → Na⁺ influx in receptor ending → graded potential → threshold? → AP in same neuron

b) Separate Receptor Cell

Stimulus → receptor cell depolarises → Ca²⁺ influx → NT exocytosis → NT binds ligand-gated Na⁺ channel on afferent ending → graded potential → threshold? → AP

Graded (Receptor) Potentials vs Action Potentials

Summation Mechanisms

• Spatial summation: ≥2 receptor sites activated simultaneously → larger combined depolarisation
• Temporal summation: single site stimulated rapidly → successive potentials superimpose → reach threshold

Quantitative Relationships

• Frequency coding: once threshold reached, AP frequency rises with receptor potential amplitude
  \text{Stronger stimulus} \;\Rightarrow\; \text{higher } V_{RP} \Rightarrow \text{higher AP Hz}

Receptor Properties & Plasticity

• Specificity – structural complementarity ligand⇌receptor
• Receptive field – physical area whose stimulation affects a single afferent (excitatory or inhibitory zones)
• Affinity
  • High affinity: tight binding, slow dissociation → prolonged effects (typical of hormones)
  • Low affinity: weak binding, rapid dissociation → fleeting effects (typical of NTs)
  • Low affinity requires ↑ ligand concentration to activate
• Equilibrium – rate of binding = rate of dissociation
• Reaction rate – speed of binding / release
• Adaptation
  • Receptor response declines during constant stimulus
  • Rapidly adapting (phasic) vs slowly adapting (tonic)
• Up-/Down-regulation
  • Chronic under-stimulation → ↑ receptor number (up-regulation)
  • Chronic over-stimulation → ↓ receptor number (down-regulation)
• Autoreceptors
  • Located presynaptically; ligand released by same neuron binds back → negative feedback to limit further release
• Death (Fas) receptors
  • Surface receptors that trigger intracellular caspase cascade → apoptosis when liganded

Neurocrine vs Endocrine Communication

Pharmacology – Agonists & Antagonists

• Agonist
  • Structural analogue; binds & activates receptor → mimics endogenous ligand
  • e.g. Thyroid hormone replacement, oral contraceptive estrogen/progesterone
• Antagonist
  • Binds receptor without intrinsic activity → blocks ligand binding/effect
  • e.g. \beta-adrenergic blockers (hypertension), tricyclic antidepressants, SSRIs
• Drug interaction governed by size, shape, charge → affinity & efficacy

Mathematical / Biophysical Tidbits

• Threshold concept visualised:
  V{rest} \approx -70\,\text{mV}, \; V{th} \approx -55\,\text{mV}
• Relationship between potential & distance in graded potentials (electrotonic spread):
  V(x) = V_0 e^{-x/\lambda}
  where \lambda = length constant

High-Yield Takeaways

• Receptors are the gatekeepers of cellular communication, converting diverse stimuli into intracellular language.
• Location dictates ligand: surface receptors ↔ hydrophilic messengers; intracellular receptors ↔ lipophilic messengers.
• Graded potentials integrate information (summation, variable amplitude) while action potentials transmit information faithfully (all-or-none).
• Adaptation ensures we are not overwhelmed by constant stimuli (clothes on skin) but can still detect new, relevant changes.
• Pharmacologically, understanding receptor classes allows strategic use of agonists or antagonists to modulate physiology.