Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that in humans is encoded by the NRG1 gene. [3] [4] NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart. [5] [6]
Neuregulin 1 (NRG1) was originally identified as a 44-kD glycoprotein that interacts with the NEU/ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing. These isoforms include heregulins (HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). They are tissue-specific and differ significantly in their structure. The HRG isoforms all contain immunoglobulin (Ig) and epidermal growth factor-like (EGF-like) domains. GGF and GGF2 isoforms contain a kringle-like sequence plus Ig and EGF-like domains; and the SMDF isoform shares only the EGF-like domain with other isoforms. The receptors for all NRG1 isoforms are the ERBB family of tyrosine kinase transmembrane receptors. Through their displayed interaction with ERBB receptors, NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells. [7]
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.
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]
| type | aliases |
|---|---|
| I | Heregulin, NEU differentiation factor (NDF), or acetylcholine receptor inducing activity (ARIA) |
| II | Glial Growth Factor-2 (GGF2) |
| III | Sensory and motor neuron-derived factor (SMDF) |
| IV | |
| V | |
| VI |
Neuregulin 1-ErbB4 interactions are thought to play a role in the pathological mechanism of schizophrenia. [12] [13] A high-risk deCODE (Icelandic) haplotype was discovered in 2002 on the 5'-end of the gene. [14] The SNP8NRG243177 allele from this haplotype was associated in 2006 with a heightened expression of the Type IV NRG1 in the brains of people suffering from schizophrenia. [15] [16] Further, the NRG1-ErbB4 signalling complex has been highlighted as a potential target for new antipsychotic treatment. [17] [18]
Additionally, Neuregulin 1 has been shown to modulate anxiety-like behaviors. Endogenous Neuregulin 1 may bind to its receptor, ErbB4, expressed on GABAergic neurons within the basolateral amygdala. Administration of exogenous Neuregulin 1 to the basolateral amygdala of anxious mice produced an anxiolytic effect, which has been attributed to the enhancement of GABAergic neurotransmission. [19] Thus, treatments aimed at reducing anxiety, which may contribute to emotional instability in many schizophrenic patients, by targeting the effects of mutations in NRG1 and ERBB4, may yield positive results for those afflicted by both anxiety disorders as well as schizophrenia.
Neuregulin has been shown to be involved in the myelination of central nervous system (CNS) axons. [20] There exist at least two modes of myelination within the CNS—one that is independent of neuronal activity and another that is promoted by the activation of NMDA receptors by glutamate on oligodendrocytes. Neuregulin is involved in the "switching" of oligodendrocytes from the mode of myelination that is independent of neuronal activity to the mode that is dependent upon glutamate binding to NMDA receptors. It is thought that Neuregulin 1 found on axons of CNS neurons interacts with its receptor, ErbB4, to promote the myelination of that axon, and any disruption in this signaling contributes to decreased myelination. [21] Since Neuregulin 1 promotes myelination and is decreased in schizophrenic patients, along with the finding that schizophrenic patients experience white matter deficits, mutations within Neuregulin 1 may underlie cognitive deficits associated with lower white matter integrity, especially within frontotemporal connections.
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 ]
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]
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]
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]
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.
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.
Neuregulin 1 has been shown to interact with ERBB3 [38] [39] [40] and LIMK1. [41] A schizophrenia associated- missense mutation in Neuregulin 1 has been shown to be associated with changes in cytokine expression using lymphoblastoid cells of heterozygous carriers vs homozygous wild type individuals [42]
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.
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger; see calcium in biology for more details). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.
Neuregulins or neuroregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.
Receptor tyrosine-protein kinase erbB-2, also known as CD340, proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 or HER2/neu.
Caveolin-3 is a protein that in humans is encoded by the CAV3 gene. Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
The activin A receptor also known as ACVR1C or ALK-7 is a protein that in humans is encoded by the ACVR1C gene. ACVR1C is a type I receptor for the TGFB family of signaling molecules.
The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2, Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.
Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it is a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.
Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.
Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the MEF2C gene. MEF2C is a transcription factor in the Mef2 family.
Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.
Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene. The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.
Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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