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

Rayudu Gopalakrishna; Narayan R. Bhat; Sarah Zhou; William J. Mack

doi:10.4103/1673-5374.255965

摘要：Various isoforms of laminins are present in the basement mem-branes complexed with other structural proteins. In the central nervous system (CNS), they are primarily localized to the base-ment membranes of blood vessels and reactive astrocytes. Limited amounts of various laminin isoforms are also associated with neu-ronal cell bodies and axons, which are referred to as "neuronal"laminins (Yamamoto et al., 1988). They exist in a soluble form, free from other basement membrane proteins. Neurons either produce these soluble laminins or acquire them from astroglial cells. Lami-nin 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 (Nelson et al., 2008), but the signaling mechanisms by which 67LR medi-ates 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 (Gopalakrishna et al., 2018). This endocytosis is dependent on adenylyl cyclase, protein kinase A, and the exchange protein directly activated by cyclic adenosine mono-phosphate (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 (Da Costa Dias et al., 2014), we postulate that laminin, by binding to and internalizing 67LR, in-hibits entry of Aβ into neurons and thereby decreases Aβ-induced neurotoxicity. Thus, laminin-related agents that induce 67LR in-ternalization could have therapeutic potential against Alzheimer’s disease (AD) and various other neurodegenerative diseases.