Description
Tesamorelin – Advanced Biochemical Mechanism Profile
(Stabilized GHRH analog; Growth Hormone–Releasing Hormone receptor agonist)
Tesamorelin is a synthetic, stabilized peptide analog of GHRH(44-amino-acid) designed to bind and activate the GHRH receptor (GHRHR) on pituitary somatotrophs.
GHRHR is a Gs-coupled GPCR whose activation drives adenylyl cyclase → cAMP accumulation → PKA signaling → CREB-mediated GH gene transcription, along with Ca²⁺-dependent vesicular release of stored growth hormone.
✅ 1. Primary Molecular Target
GHRH Receptor (GHRHR)
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Class B GPCR
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Coupled predominantly to Gsα
Activation Sequence:
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Tesamorelin binds GHRHR extracellular domain
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Gsα activation → adenylyl cyclase stimulation
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↑ cAMP
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PKA activation
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Phosphorylation of ion channels and SNARE-machinery
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Exocytosis of GH vesicles
✅ 2. Core Intracellular Signaling Cascades
A. cAMP → PKA → CREB (Primary Pathway)
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cAMP increase activates PKA
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PKA phosphorylates CREB
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CREB binds promoters of GH-related genes
CREB-regulated gene targets:
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GH1 (growth hormone)
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POU1F1 (PIT-1) – master GH transcription factor
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GHRHR (autoregulation)
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IGF-1 & IGF-1R (secondary endocrine axis)
B. Ca²⁺-Dependent Exocytosis
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PKA enhances L-type Ca²⁺ channel activity
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Ca²⁺ influx triggers SNARE-complex function:
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Synaptotagmin (SYT)
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SNAP-25
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Syntaxin (STX)
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VAMP2
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Result: fusion of GH-containing vesicles with the plasma membrane.
C. MAPK / ERK1/2 Crosstalk
GHRHR stimulation also engages:
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Ras → Raf → MEK → ERK1/2
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ERK nuclear translocation induces immediate-early gene transcription
Representative ERK-responsive genes:
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FOS
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JUN
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EGR1
✅ 3. Second Messenger Systems
| Second Messenger | Function in Tesamorelin Signaling |
|---|---|
| cAMP ↑ | Initiates GH transcription and exocytosis |
| PKA | Ion channel regulation, CREB phosphorylation |
| Ca²⁺ flux | Vesicular fusion and peptide release |
| ERK1/2 | Cell-growth and differentiation genes |
✅ 4. Enzymes & Molecular Effectors
| Enzyme/Component | Mechanistic Role |
|---|---|
| Adenylyl cyclase | Converts ATP → cAMP |
| Protein Kinase A (PKA) | Regulates Ca²⁺ channels, CREB, SNARE complex |
| Phospholipase C (minor GC-linked arm) | IP₃-mediated Ca²⁺ release |
| SNARE proteins | GH vesicle fusion/exocytosis |
| ERK1/2 MAPKs | Transcription of mitogenic genes |
✅ 5. Representative Gene Targets
| Functional Class | Key Genes Affected |
|---|---|
| GH synthesis | GH1, POU1F1 (PIT-1), GHRHR |
| Growth factor axis | IGF-1, IGF-1R |
| Vesicle release machinery | SNAP25, SYT1, VAMP2 |
| MAPK-responsive | FOS, JUN, EGR1 |
✅ Mechanistic Summary
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Tesamorelin is a GHRH receptor agonist
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Activates Gs → adenylyl cyclase → cAMP → PKA
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Triggers Ca²⁺-dependent GH exocytosis
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Drives CREB-mediated GH gene transcription
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Engages ERK1/2 for mitogenic and differentiation signaling
Research-Only Classification
Tesamorelin is provided exclusively for controlled in-vitro laboratory research.
Not authorized for human or animal administration, therapeutic use, or any biological application outside research.
