Description

Semaglutide – Advanced Biochemical Mechanism & Pathway Profile

(Long-acting GLP-1 Receptor Agonist – Peptide Analogue)

Semaglutide is a synthetic GLP-1 analogue engineered for prolonged stability and extended receptor engagement. It exhibits high affinity for the GLP-1 receptor (GLP-1R), a Class B G-protein–coupled receptor (GPCR) expressed in pancreatic, hepatic, gastrointestinal, and central nervous system cell models.

✅ Primary Receptor Target

GLP-1R (Gs-coupled GPCR)

Binding leads to activation of adenylate cyclase, cAMP accumulation, and PKA signaling, followed by phosphorylation of transcriptional regulators.

• ↑ cAMP

• ↑ PKA activation

• ↑ EPAC2 signaling

• ↑ Ca²⁺ influx via voltage-gated Ca²⁺ channels

✅ Core Intracellular Signaling Cascades

1. cAMP → PKA → CREB Pathway

• Semaglutide → GLP-1R → Gs → Adenylate cyclase

• cAMP increases, activating:

  • Protein kinase A (PKA)

  • Exchange protein activated by cAMP 2 (EPAC2)

Downstream transcription factor:

• CREB phosphorylation → transcription of CRE-regulated genes

Genes studied:

• POMC, CART, BDNF (CNS metabolic signaling)

• IRS2, PDX1 (insulin signaling pathways)

• GLUT2, GCK (glucose transport/metabolism)

2. PI3K / Akt Pathway

Although GLP-1R does not bind insulin receptors, crosstalk has been observed through:

• cAMP → PI3K activation

• PI3K → Akt phosphorylation

• Akt → inhibition of GSK-3β

• Akt → modulation of FoxO transcription factors

Gene targets monitored:

• INS, GLUT2, GCK

• Cellular survival and mitochondrial signaling genes

3. MAPK / ERK Pathway

Semaglutide-stimulated GLP-1R can activate:

• Ras → Raf → MEK1/2 → ERK1/2

• ERK-dependent transcriptional programs

• Neuronal plasticity and metabolic adaptation genes

✅ Calcium-Dependent Signaling

GLP-1R activation increases:

• Voltage-gated Ca²⁺ influx

• Ca²⁺/calmodulin-activated protein kinases (CaMK)

• Vesicular exocytosis of secretory granules (in endocrine research)

✅ Receptor Kinetics

Semaglutide incorporates structural modifications that:

• Increase resistance to DPP-4 enzymatic cleavage

• Promote albumin binding, slowing renal clearance

• Prolong receptor activation and cAMP signaling duration

✅ Downstream Molecular Targets (Condensed Table)

Research-Only Classification

Semaglutide is supplied solely for in-vitro laboratory research.
It is not approved for human or animal consumption, injection, ingestion, or diagnostic or therapeutic use.