The neuronal insulin receptor in its environment

Abstract

Insulin is known mainly for its effects in peripheral tissues, such as the liver, skeletal muscles and adipose tissue, where the activation of the insulin receptor (IR) has both short-term and long-term effects. Insulin and the IR are also present in the brain, and since there is evidence that neuronal insulin signaling regulates synaptic plasticity and that it is impaired in disease, this pathway might be the key to protection or reversal of symptoms, especially in Alzheimer's disease. However, there are controversies about the importance of the neuronal IR, partly because biophysical data on its activation and signaling are much less complete than for the peripheral IR. This review briefly summarizes the neuronal IR signaling in health and disease, and then focuses on known differences between the neuronal and peripheral IR with regard to alternative splicing and glycosylation, and lack of data with respect to phosphorylation and membrane subdo-main localization. Particularities in the neuronal IR itself and its environment may have consequences for downstream signal-ing and impact synaptic plasticity. Furthermore, establishing the relative importance of insulin signaling through IR or through hybrids with its homolog, the insulin-like growth factor 1 receptor, is crucial for evaluating the consequences of brain IR activation. An improved biophysical understanding of the neuronal IR may help predict the consequences of insulin-targeted interventions. Abbreviations used: AD, Alzheimer's disease; AbO, b-amyloid oligomer; AMPAR, a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor; ERK, extracellular signal-regulated kinase; GABA A R, c-aminobutyric acid receptor, class A; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IR-A, isoform A of the insulin receptor; IRS, insulin receptor substrate; NMDAR, N-methyl-D-aspartate receptor; PI3K, phosphatidylinositol-4,5-bisphosphate-3-kinase; Shc, Src homology 2 domain containing.

Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

“…Given the marked downregulation of INSR expression and signaling in horizontal cell axons and terminal tips that accompanies rod degeneration, together with the role of INSR in synapse formation and maintenance (Chiu & Cline, 2010, Gralle, 2017, Lee et al, 2011, we next investigated whether changes in INSR expression coincided with alterations in synaptic structure in the OPL. Our analyses focused on rod synapses, since cone survival remains uncompromised in the early stages of degeneration in the rd10 retina (Zhao, Zabel et al, 2015).…”

“…The versatility of this receptor is also implied by its widespread expression in the CNS. At the neuronal level, INSR has been implicated in synaptic plasticity, dendritic outgrowth, and cell survival (Chiu & Cline, 2010, Gralle, 2017, Lee et al, 2011. The Insr-a splice variant, which is predominantly expressed in different areas of the brain as well as the retina, is the most ancient and promiscuous isoform, and participates in insulin, Pi, and IGF-II signaling (Hernandez-Sanchez et al, 2008, Malaguarnera et al, 2012.…”

“…Since initial reports described widespread INSR expression in the CNS, including the retina (de la Rosa, Bondy et al, 1994, Havrankova, Roth et al, 1978, Marks, Porte et al, 1990, Rodrigues, Waldbillig et al, 1988, Unger, McNeill et al, 1989, INSR signaling has been implicated in a growing number of CNS functions. In addition to regulating feeding behavior and peripheral metabolism, central INSR signaling is involved in memory formation and cognitive functions (Arnold et al, 2018, Banks et al, 2012, Gralle, 2017. The mechanisms underpinning the non-metabolic actions of INSR are being gradually unraveled.…”

Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

“…Analysis of synaptic ultrastructure in the OPL of WT and rd10 retinas Given the marked downregulation of INSR expression and signaling in horizontal cell axons and terminal tips that accompanies rod degeneration, together with the role of INSR in synapse formation and maintenance [8,14,15], we next investigated whether changes in INSR expression coincided with alterations in synaptic structure in the OPL. Our analyses focused on rod synapses, since cone survival remains uncompromised in the early stages of degeneration in the rd10 retina [40].…”

“…Since initial reports described widespread INSR expression in the CNS, including the retina [9][10][11][12][13], INSR signaling has been implicated in a growing number of CNS functions. In addition to regulating feeding behavior and peripheral metabolism, central INSR signaling is involved in memory formation and cognitive functions [6,7,14]. The mechanisms underpinning the non-metabolic actions of INSR are being gradually unraveled.…”