Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

Abstract

Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly‐N‐acetyllactosamine chain of d‐galactose‐GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi‐sulfated high‐charge density, monosulfated and non‐sulfated poly‐N‐acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit‐Robbo and Ephrin‐Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS‐PG abakan defines functional margins of the brain and is up‐regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti‐oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK‐1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS‐PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS‐PGs in development and regenerative neural processes.

Electro‐Stimulation, a Promising Therapeutic Treatment Modality for Tissue Repair: Emerging Roles of Sulfated Glycosaminoglycans as Electro‐Regulatory Mediators of Intrinsic Repair Processes

“…[ 46,47 ] KS is a widely distributed GAG in sensory tissues and displays variable sulfation levels which may facilitate fine levels of control over the counterions they make available for the generation of ion channel generated events in specific developmental contexts. [ 10,24,25,48 ]…”

“…Mucinous deposits have also been observed surrounding sensory cilia on neurosensory cells in mammals and these are decorated with sialic acid and KS which have roles in the conduction of electro‐sensory signals to interconnected neurons in a number of sensory tissues. [ 25,46 ] The conductive properties of KS substituted mucin glycopolymers synthesized by tumor cells has also been exploited in the development of electro‐chemical biosensors which detect the conductive polymers produced by the tumor cells in secretions and biological fluids and can be used prognostically to assess disease status. [ 64 ]…”

“…[ 55,56,65 ] The predominance of KS substituted molecules in neural tissues also testifies to the unique functional properties conveyed by this GAG in sensory processes. [ 25,46,47,55,56 ] In weakly electric fish species which employ electro‐location or electro‐communication, a characteristic electric oscillatory discharge is generated and emitted by a pacemaker organ. This electrical discharge can be modulated in terms of its amplitude, frequency and the waveform of the signal elicited and other fish can interpret this signal which thereby forms a sophisticated means of social communication.…”

“…As stated previously, the GAG glyco‐code evolved over several hundred million years of evolution as a cell regulatory mechanism involved in tissue development, physiology, and repair. [ 1,10,12,18,22,23,24,25 ] The longevity of GAGs over this protracted evolutionary period points to the essential roles they played in essential cellular survival processes. [ 1 ] The sulfation patterns on GAGs direct these cellular molecular recognition activities.…”

“…[ 1 ] The sulfation patterns on GAGs direct these cellular molecular recognition activities. [ 10,18,23,24,25 ] Deciphering of the glyco‐code using sophisticated techniques [ 26 ] demonstrates the significant cell regulatory properties and biodiversity of these molecules [ 1,27 ] and the recognition of diverse roles for GAGs in cellular regulatory processes in health and disease. [ 22,28 ] This has led to the development of bioscaffolds containing bio‐directive GAGs to guide cellular activities in an effort to promote tissue repair and regeneration.…”