Neuregulin (NRG)are trophic factors that belong to the epithelial growth factor (EGF) family responsible for growth and differentiation of epithelial, glial, and muscle cells.
The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. This family of genes has four members: NRG1, NRG2, NRG3, and NRG4. they bind to and activate the erbB family of receptor tyrosine kinases (erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4)), functioning both as heterodimers and homodimers.
The NRG1 gene is located on the short (p) arm of chromosome 8 at position 12.
Protein Aminoacids Percentage (Width 700 px)
NRG isoforms are expressed mainly by cells of endothelial, mesenchymal, and neuronal origin and are thus critical for the proliferation, survival, migration, and differentiation of several cell types.
Neuregulin1 is a protein which in humans is encoded by the NRG1 gene and is produced in numerous isoforms by alternative splicing that include:
- Acetylcholine receptor-inducing activity (ARIA)
- Heregulins (HRGs)
- Glial growth factors (GGFs)
- Neu differentiation factor (NDF)
- Sensory and motor neuron-derived factor (SMDF)
It is essential for the normal development of the nervous system and the heart; there is also evidence for involvement of NRG signaling in the development and function of several other organ systems and in human disease, including the pathogenesis of schizophrenia and breast cancer.
Neuregulin 1 was originally identified as a 44-kD glycoprotein that interacts with the NEU/ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues.
Schizophrenia is a highly heritable psychiatric illness that affects 1% of psychotic symptoms, principally delusions and hallucinations. The etiology of schizophrenia remains uncertain, but abnormalities in brain structure and function have been consistently demonstrated, particularly in the frontal and temporal lobes.
NRG1 is a promising candidate susceptibility gene for schizophrenia with a range of roles in nervous system development and plasticity.The potential pathophysiologic role of NRG1 is further supported by its diverse neurobiological functions that include:
- Neuronal migration
- Neuro-glial trophic effects
- Modulation of glutamatergic and or GABAergic neurotransmitter systems.
Genetic evidence also supports erbB4 as a candidate susceptibility gene and suggests positive epistatic interactions between NRG1 and erbB4 in schizophrenia.The tyrosine kinase receptor, erbB4, along with erbB2 and erbB3, transduces neuregulin1 and influences glutamatergic and GABAergic transmission as well as neurotrophic effects, which have also been implicated in schizophrenia.
Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia
NRG plays a crucial role in myogenesis in skeletal muscle.
It has long been observed that nerves have the capacity to stimulate skeletal muscle growth and maintenance in an electrical stimuli-independent fashion but are dependent on some myotrophic agents; GGF2, one of the NRG isoforms generated by neurons, was identified as a myogenic factor and acts in an additive manner with insulin-like growth factor I (IGF-I).
Studies showed that NRG is released by these cells at the initial stage of myogenesis, and, acting in an autrocrine manner through ErbB3, they are essential for myogenic differentiation.
As a myogenic factor, NRG-1 promotes myogenin expression, thereby prompting myoblasts to withdraw from the cell cycle and differentiate, thus inducing fusion to multinucleated myotubes. NRG also induces muscle spindle formation and plays a positive role in intrafusal fiber development by increasing nuclear bag fiber formation.
NRG also plays a relevant role in muscle regeneration.
From a Myogenic Factor to a Metabolic Regulator Involved in Contraction Events
NRG involvement in muscle contraction effects on the regulation of GLUT4 translocation in a calcium (Ca2+)-dependent manner. Muscle contraction induces an increase in cytosolic calcium, which activates membrane metalloproteinase, which in turn cleaves and releases the NRG extracellular region that contains the EGF domain. The EGF domain binds to ErbB4/ErbB2 heterodimeric receptors, which then become tyrosine phosphorylated (Y-P), thereby inducing a signaling cascade. PKCζ, but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) or AMP-activated protein kinase (AMPK), is activated by NRG translocation of GLUT4 storage vesicles to increase glucose transport.