Neuregulin 1

Neuregulin 1, or NRG1, is a gene of the

Neuregulin 1 is thought to play a role in synaptic plasticity. It has been shown that a loss of Neuregulin 1 within cortical projection neurons results in increased inhibitory connections and reduced synaptic plasticity.[8] Similarly, overexpression of Neuregulin 1 results in disrupted excitatory-inhibitory connections, reduced synaptic plasticity, and abnormal dendritic spine growth. Mutations in human L1 cell adhesion molecules are reported to cause a number of neuronal disorders. In addition, recent research in Drosophila model has also shown Nrg's involvement in regulating dendritic pruning in ddaC neurons in a Rab5/ESCRT-mediated endocytic pathway.^[9] Thus, careful regulation of the amount of Neuregulin 1 must be maintained in order to preserve an intricate balance between excitatory and inhibitory connections within the central nervous system (CNS). Any disruption in this inhibitory system may contribute to impaired synaptic plasticity, a symptom endemic in schizophrenic patients.

Isoforms

At least six major types (different N termini) of neuregulin 1 are known.^[10] Six types exist in humans and rodents (type I, II and III NRG1 are expressed in excitatory and inhibitory neurons, as well as astrocytes), and some types (I and IV) can be regulated by neuronal activity.^[11]

Clinical significance

Neuregulin 1-

The protein also has the putative ability to protect the brain from damage induced by stroke.[22] Those with a genetic variant of neuregulin 1 tended to be more creative.^[23]

There is evidence that NRG1 is a tumor suppressor gene.^[24]

There is also strong evidence that NRG1 plays a critical role in Schwann cell maturation, survival, and motility,^[25] important in research related to neurofibromatosis type two (NF2).^{[citation needed]}

Heart

Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, is necessary for cardiac development, structural maintenance, and functional integrity of the heart. NRG-1 and its receptor family ErbB can play a beneficial role in the treatment of chronic heart failure (CHF) by promoting survival of cardiac myocytes, improving sarcomeric structure, balancing Ca2+ homeostasis, and enhancing pumping function. Downstream effectors of NRG-1/ErbB, include cardiac-specific myosin light chain kinase (cMLCK), Protein Phosphatase type 1 (PP1), sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2), and focal adhesion kinase (FAK). The beneficial effects of neuregulin-1 make recombinant human neuregulin-1 (rhNRG-1) a potential drug for treatment of CHF.^[26]

Maintenance of heart structure

NRG-1 treatment of adult rat ventricular myocytes stimulate the formation of a multiprotein complex between ErbB2, FAK, and p130(CAS), which modulates the restoration of cell–cell contacts between isolated myocytes, allowing for synchronous beating.^[27] Furthermore, FAK is also involved in the maintenance of sarcomeric organization, cell survival, and myocyte–myocyte interactions.^[28] The sarcomeric effects of NRG-1 protects myocytes against structural disarray induced by stressors, including cytotoxic agents.^[29]

Cardiomyocyte survival under stress

Under conditions of stress, including viral infection, cytotoxic agents, and oxidative stress, activation of NRG-1/ErbB signaling can protect myocardial cells against apoptosis.^[27] In contrast to embryonic and neonatal cardiomyocytes, adult myocardial cells are terminally differentiated and have lost the ability to proliferate. Therefore, growth of adult cardiac cells is commonly characterized by hypertrophy and an increased content of contractile proteins.^[30] However, studies have shown NRG-1 promotes myocardial regeneration through hyperplasia, and prevents hypertrophy surrounding infarcted areas.^[31]

Restoration of cardiomyocytes

The cMLCK protein is an important regulator of sarcomere assembly through activation of the myosin regulatory light chain, as well as playing a role in heart contractility.^[32][33] In contrast to smooth and skeletal muscle MLCKs, cMLCK expression is restricted to cardiac myocytes.^[33] Overexpression of cMLCK increases cell contractility.^[32] Treatment of cardiac myocytes with rhNRG-1 significantly upregulated cMLCK expression or activity??? in CHF rat models, together with an improvement in both cardiomyocyte structure and pumping function.^[26] Therefore, cMLCK is a downstream protein regulated by NRG-1/ErbB signaling and plays a role in rhNRG-1-mediated improvements in CHF.

Improvements in cardiac efficiency

Altered calcium homeostasis has been suggested to play a role in the development of heart failure. Modulated by phospholamban (PLB), SERCA2 regulates uptake of Ca2+ into the sarcoplasmic reticulum (SR) from the cytoplasm and contributes to the relaxation of cardiomyocytes.^[34] This process is also important for determining the SR Ca2+ load after relaxation and, thus, impacts on contractility.^[34][35] PP1 dephosphorylates PLB, inhibiting SERCA2 activity.^[36] In the failing heart, PP1 expression is upregulated, resulting in increased PLB dephosphorylation and decreased SERCA2 activity.^[37] Preliminary studies have revealed that rhNRG-normalizes SERCA function and enhances myocardial contractility through the inhibition of increasedPP1 expression, which leads to increased PLB phosphorylation and activation of SERCA2.

Interactions

Neuregulin 1 has been shown to

Specifically, the missense mutation involves a single nucleotide change of a valine to a leucine within the transmembrane domain of Type 3 Neuregulin 1. It is thought that this single nucleotide change affects the ability of γ-secretase to cleave the intracellular domain (ICD) of the Type 3 isoform of Neureglin 1.^[43] That is, the valine to leucine mutation within the transmembrane domain of Type 3 Neuregulin 1 decreases the amount of ICD that γ-secretase is able to cleave. The ICD of Type 3 Neuregulin 1 has been shown to suppress transcription of inflammatory cytokines, including IL-1β, IL-6, IL-10, IL-8, IL12-p70, and TNF-α. Using recombinant ErbB4 to stimulate the cleavage of the intracellular domain of Type 3 Neuregulin 1, a receptor for Type 3 Neuregulin 1, Marballi et al. showed that increased levels of the ICD lead to a decrease in IL-6 levels. Given the involvement of Neuregulin 1 in schizophrenia and the finding that the valine to leucine missense mutation in mice produces working memory deficits,^[44] NRG1 seems a likely genetic candidate that confers susceptibility to the development of schizophrenia.

References