中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (9): 1513-1514.doi: 10.4103/1673-5374.255965

• 观点:退行性病与再生 • 上一篇    下一篇

可溶性层粘连蛋白与67KDa层粘连蛋白受体内化相关的细胞信号转导及其对神经退行性疾病的保护作用

  

  • 出版日期:2019-09-15 发布日期:2019-09-15

Cell signaling associated with internalization of 67 kDa laminin receptor (67LR) by soluble laminin and its implication for protection against neurodegenerative diseases

Rayudu Gopalakrishna 1, Narayan R. Bhat 3, Sarah Zhou 1, William J. Mack 2   

  1. 1 Department of Integrative Anatomical Sciences, Keck School of Medicine, Los Angeles, CA, USA;
    2 Department of Neurological Surgery, Keck School of Medicine, Los Angeles, CA, USA;
    3 Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
  • Online:2019-09-15 Published:2019-09-15
  • Contact: Rayudu Gopalakrishna, PhD, rgopalak@usc.edu.

摘要:

orcid: 0000-0002-0398-3166 (Rayudu Gopalakrishna)

Abstract:

Various isoforms of laminins are present in the basement membranes complexed with other structural proteins. In the central nervous system (CNS), they are primarily localized to the basement membranes of blood vessels and reactive astrocytes. Limited amounts of various laminin isoforms are also associated with neuronal cell bodies and axons, which are referred to as “neuronal” laminins. They exist in a soluble form, free from other basement membrane proteins. Neurons either produce these soluble laminins or acquire them from astroglial cells. Laminin stimulates neuritogenesis and confers neuroprotection in vitro, but their exact role of these neuronal soluble laminins in the CNS is yet unknown. Laminins bind to various cell-surface receptors including integrins, dystroglycan, and the nonintegrin type 67 KDa laminin receptor (67LR). In neurons, it is well known that 67LR internalizes prion proteins and various bacteria and viruses but the signaling mechanisms by which 67LR mediates neuroprotection, particularly by soluble laminin, is not clearly known. Recently, we have found that soluble laminin (laminin-1 isoform) as well as its YIGSR pentapeptide corresponding to the 67LR-binding sequence present in the β1-chain of laminin, which can induce internalization of 67LR. This endocytosis is dependent on adenylyl cyclase, protein kinase A, and the exchange protein directly activated by cyclic adenosine monophosphate (cAMP) (Epac). The internalized endosomes comprising adenylyl cyclase and other signaling enzymes, continue to generate signals such as cAMP for a sustained period of time which may contribute to neuroprotection. Considering that β-amyloid peptide (Aβ) is internalized through 67LR, we postulate that laminin, by binding to and internalizing 67LR, inhibits entry of Aβ into neurons and thereby decreases Aβ-induced neurotoxicity. Thus, laminin-related agents that induce 67LR internalization could have therapeutic potential against Alzheimer’s disease (AD) and various other neurodegenerative diseases.