Bioactive Peptides and Signaling Pathways

Bioactive peptides are signaling molecules that regulate virtually every physiological process in the human body.

What Makes a Peptide Bioactive?

Definition - 2-50 amino acids - Specific biological activity - Acts through receptors - Distinct from structural/enzymatic proteins

Types by Function 1. **Hormones** — Systemic signals (insulin, glucagon) 2. **Neuropeptides** — Neural modulators (endorphins, NPY) 3. **Local mediators** — Paracrine signals (bradykinin) 4. **Antimicrobial** — Defense molecules (defensins)

Signaling Through GPCRs

~80% of peptide hormones act through G-Protein Coupled Receptors

GPCR Activation 1. Peptide binds extracellular domains 2. Receptor conformational change 3. G-protein activation (α subunit releases GDP/binds GTP) 4. Effector activation

G-Protein Subtypes

Downstream Effects - **cAMP** → PKA activation → phosphorylation - **Ca²⁺/IP₃** → Calcium release → varied effects - **DAG** → PKC activation → phosphorylation

Receptor Tyrosine Kinases (RTKs)

Larger peptides like insulin use RTKs:

Mechanism 1. Peptide binding causes receptor dimerization 2. Autophosphorylation of tyrosine residues 3. Recruitment of signaling proteins (IRS, PI3K) 4. Activation of downstream cascades (Akt, MAPK)

Major Peptide Signaling Families

Metabolic Peptides

• Source: Pancreatic β-cells
• Receptor: Insulin receptor (RTK)
• Effects: Glucose uptake, glycogen synthesis

• Source: Intestinal L-cells
• Receptor: GLP-1R (GPCR, Gαs)
• Effects: Insulin secretion, satiety

Neuropeptides

• Receptors: μ, δ, κ opioid (GPCR, Gαi)
• Effects: Pain modulation, reward

• Receptors: Y1-Y5 (GPCR)
• Effects: Appetite stimulation, anxiety

Cardiovascular Peptides

• Receptor: AT1 (GPCR, Gαq)
• Effects: Vasoconstriction, aldosterone release

• Receptor: NPR-A (guanylyl cyclase)
• Effects: Vasodilation, natriuresis

Signal Termination

Peptide Degradation - DPP-IV cleaves GLP-1 (~2 min half-life) - Neprilysin degrades natriuretic peptides - ACE cleaves angiotensin I to angiotensin II

Receptor Desensitization - Phosphorylation by GRKs - β-arrestin binding - Receptor internalization - Recycling or degradation

Biased Agonism Modern concept: Different ligands stabilize different receptor conformations - Can selectively activate G-protein OR β-arrestin pathways - Therapeutic implications for side effect reduction

Key Signaling Peptides