The neuronal insulin receptor in its environment - Wiley Online Library

JOURNAL OF NEUROCHEMISTRY

| 2017 | 140 | 359–367

doi: 10.1111/jnc.13909

Instituto de Bioquımica Medica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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 subdomain localization. Particularities in the neuronal IR itself and its environment may have consequences for downstream signaling 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 insulintargeted interventions. Keywords: Alzheimer’s disease, dendritic spine, glycosylation, membrane domain, splicing, synaptic plasticity. J. Neurochem. (2017) 140, 359–367.

Insulin in the brain

et al. 2005; Lee et al. 2005, 2011; Caraiscos et al. 2007; Chiu et al. 2008; Jin et al. 2011; Dixon-Salazar et al. 2014; Grillo et al. 2015). In the most common experimental paradigm, an acute synaptic effect is measured upon the addition of insulin to a model system. This is an appropriate paradigm for neurotransmitters or neuromodulators with strongly varying receptor site concentrations. However, while a transmitterlike release of insulin from neurogliaform cells has recently

The insulin receptor (IR) is a tyrosine kinase receptor that transmits the binding of extracellular ligands of the insulin family into several intracellular signaling cascades, resulting in both short-term metabolic effects and longer term effects on development and growth (Hubbard 2013; Bedinger and Adams 2015; De Meyts 2015; Tatulian 2015). In addition to the classic insulin target tissues, such as the muscle, adipose tissue, liver and pancreas, insulin and the IR are also present in the brain (Ghasemi et al. 2013; Kleinridders et al. 2014), and over the last 20 years, many studies have suggested that insulin acting on a neuronal receptor regulates synaptic plasticity (Fig. 1), both by regulating the uptake, release and degradation of the neurotransmitters norepinephrine and dopamine (Sauter et al. 1983; Boyd et al. 1985; K€onner et al. 2011; Kleinridders et al. 2015) and by regulating the sensitivity of post-synaptic receptors (Liu et al. 1995; Wan et al. 1997; Christie et al. 1999; Zhao et al. 1999; Beattie et al. 2000; Man et al. 2000; Passafaro et al. 2001; Skeberdis et al. 2001; Huang et al. 2003; O’Malley et al. 2003; Ahmadian et al. 2004; Dou

Received August 4, 2016; revised manuscript received October 31, 2016; accepted November 21, 2016. Address correspondence and reprint requests to Matthias Gralle, Centro de Ciências da Saude, Av. Carlos Chagas Filho 373, Rio de Janeiro, RJ, CEP 21941-590, Brazil. E-mail: [email protected] 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; GABAAR, c-aminobutyric acid receptor, class A; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IRA, isoform A of the insulin receptor; IRS, insulin receptor substrate; NMDAR, N-methyl-D-aspartate receptor; PI3K, phosphatidylinositol4,5-bisphosphate-3-kinase; Shc, Src homology 2 domain containing.

© 2016 International Society for Neurochemistry, J. Neurochem. (2017) 140, 359--367

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been shown (Molnar et al. 2014), it appears that at most a small fraction of insulin in the brain (outside the hypothalamus) derives from rapid release by brain cells; the main fraction of brain insulin is probably transported over the blood–brain barrier and then diffuses passively (Gray et al. 2014). Since insulin concentrations in the synaptic cleft have not been measured during neuronal activity, it is difficult to tell if insulin levels near brain IRs vary enough to modulate their activation over the short term; however, very sharp increases in serum insulin (higher than those seen in the healthy post-prandial condition) have no effect at all on total brain insulin content (Banks et al., 1997) nor on hippocampus interstitial fluid concentration in mice (Stanley et al., 2016). Nevertheless, the expression level and insulin sensitivity of the hippocampal IR itself increase during learning; this will affect downstream signals regardless of changes in insulin concentration (Zhao et al. 1999; Dou et al. 2005). Mechanisms capable of regulating the IR (neuronal and peripheral) in such a manner have been discovered: presenilins reduce hippocampal IR expression (Maesako et al. 2011), while the active conformation of the neuronal IR is inhibited by direct contact with major histocompatibility complex class I proteins (Dixon-Salazar et al. 2014). Regardless of the mechanism of neuronal insulin signaling, the importance of the neuronal insulin receptor for cognition can no longer be denied. Whole-body haploinsufficiency in the IR manifests with learning and memory problems (Nistico et al. 2012), although this may be because of indirect effects of peripheral IR insufficiency (Sallam et al. 2015). In fact, the lack of cognitive problems in neuronspecific IR knock-out mice (Bruning et al. 2000; Schubert et al. 2004) led to some doubts about the importance of the neuronal IR for cognition (Bedinger and Adams 2015). However, a very recent adult hippocampal IR knockdown model does indeed show impaired synaptic plasticity, suggesting that the lack of cognitive symptoms in the knock-out model is most probably a result of developmental compensation (Grillo et al. 2015).

IR in Alzheimer’s disease The exact mechanism of brain insulin signaling is clinically relevant, since it has been reported that neuronal insulin signaling is impaired in dementia (Stoeckel et al. 2016); the reduction in IR expression by presenilin, and the repression of an active IR conformation by major histocompatibility complex class I, as mentioned in the previous section, were suggested to contribute to the causative role of presenilins and of brain inflammation in Alzheimer’s disease (AD) (Maesako et al. 2011; Dixon-Salazar et al. 2014). Intervention in neuronal insulin signaling has been suggested to be a key to protection against or reversal of AD symptoms (Craft et al. 2012; Hölscher 2014). In small-scale clinical trials,

intranasal treatment with insulin or insulin analogs has afforded some degree of memory improvement or of protection against cognitive deterioration, but often only for a subgroup of patients: in short-term studies, carriers of the APOE e4 allele (the major genetic risk factor for sporadic AD) benefitted less than non-carriers or even worsened upon insulin treatment (Reger et al. 2006, 2008), while in other longer term studies, the e4 non-carriers in general (Claxton et al. 2015) or the female e4 non-carriers (Claxton et al. 2013) worsened in comparison to placebo. Defects in insulin signaling might impact dementia in several ways, e.g. by reducing NMDA-mediated synaptic transmission (Grillo et al. 2015); in addition, such defects increase the binding of b-amyloid oligomers (AbOs), which are widely accepted as causal agents for Alzheimer’s disease, to the neuronal plasma membrane (De Felice et al. 2009; Zhao et al. 2009). Conversely, neuronal surface expression of IR is strongly, but indirectly reduced by AbOs (Zhao et al. 2008; De Felice et al. 2009). The context of these findings is that several synaptic membrane proteins have been proposed to fulfill the function of AbO receptor, including the prion protein and metabotropic glutamate receptor 5 (Lauren et al. 2009; Renner et al. 2010; Haas and Strittmatter 2016), a-amino-3-hydroxy-5-methylisoxazole-4propionate receptor (AMPAR) (Zhao et al. 2010) and NMDAR (De Felice et al. 2007; Decker et al. 2010). Since each of these proteins seems to be important for AbO binding, possibly several of them combine to form a macromolecular AbO receptor complex at the post-synaptic density, which might then affect and be affected by insulin signaling (Ferreira and Klein 2011). It is, however, noteworthy that chronic reduction in neuronal insulin signaling in IR-deficient mice reduces the hippocampal load of AbOs (St€ ohr et al. 2013).

IR signaling The IR exists as a preformed disulfide bond-linked dimer (Fig. 1), where each protomer contains two chains (a and b) derived from the same gene product (Hubbard 2013). Structural studies have shown how a single molecule of the ligand insulin binds in different ways to the two extracellular domains of the receptor dimer (Ward et al. 2013; De Meyts 2015). Insulin binding then leads to reciprocal phosphorylation of Tyr residues in the intracellular domains and to interaction with several intracellular proteins, some of which are themselves Tyr-phosphorylated by the IR (Hubbard 2013). The signaling pathways activated by binding of insulin to its receptor have been reviewed before in great detail. Briefly, the signal from activation of the IR is transmitted either through the family of insulin receptor substrates (IRSs) to phosphatidylinositol-4,5-bisphosphate-3kinase (PI3K), leading, in classical insulin target tissues, to largely short-term metabolic effects; or it is transmitted


Neuronal insulin receptor in its environment

through IRS and/or Src homology 2 domain containing family members to extracellular signal-regulated kinases (ERK) having, in those tissues, mainly mitotic effects (Belfiore et al. 2009; Bedinger and Adams 2015). There is evidence that both these pathways are involved in synaptic effects of insulin (Zhao et al. 1999; Dou et al. 2005; Townsend et al. 2007; Kleinridders et al. 2014; see Fig. 1); an insulin-triggered increase in synaptic density may require PI3K, not ERK activity (Lee et al. 2011), while an insulin-specific dampening of Ca2+ oscillations requires ERK, not PI3K activity (O’Malley et al. 2003). Real-time measurements of the action of insulin on the synaptic IR at physiological concentrations might further clarify the importance of the different downstream pathways. Several preclinical researchers in the Alzheimer field have focused on reverting downstream signaling defects in the IRS pathway, which is the one most strongly affected in peripheral insulin resistance (Bomfim et al. 2012; Talbot et al. 2012; Long-Smith et al. 2013; Lourenco et al. 2013). The agonist that reduces IRS-1 defects does indeed also show therapeutic promise in Alzheimer’s disease patients, although the clinical effect has not been shown to be associated with changes in insulin signaling (Gejl et al. 2016). It is important to consider that downstream insulin signaling in the brain differs in several aspects from that in the periphery (Gupta and Dey 2012). Furthermore, the clear inactivation of Akt, a major downstream target of the IRSs, in neuronal-specific IR knock-out mice was not associated with defects in hippocampal learning and memory, the typical symptoms of Alzheimer’s disease, but with mood changes (Schubert et al. 2004; Kleinridders et al. 2015).

Differences between neuronal and peripheral IR In peripheral tissues, especially in the muscle and adipose tissue, activation of the IR has short-term metabolic effects, most importantly the insertion of glucose transporters into the plasma membrane (Bedinger and Adams 2015). While insulin regulates glucose uptake by glia (Clarke et al. 1984), even very high insulin concentrations do not raise glucose uptake by neurons above baseline levels (Boyd et al. 1985; Werner et al. 1989; Duarte et al. 2006); insulin may instead modulate synaptic plasticity (Chiu and Cline 2010). Thus, what are the particularities of the neuronal IR and its environment? The phosphorylation of numerous IR tyrosine, serine and threonine residues on the IR is regulated by different ligands and proteins (Youngren 2007). In cell lines, it has been shown that tyrosine phosphorylation rates influence the internalization of IR-A, which may regulate the predominance of PI3K versus ERK downstream signaling (Rajapaksha and Forbes 2015). The phosphorylation pattern of the IR varies strongly among tissues and animal models (Issad et al. 1991; Coba et al. 2004), but site-specific phosphorylation of the IR and the IRSs has not been measured systematically in

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neurons; especially desirable would be high-resolution techniques such as 2D chromatography (Issad et al. 1991) or mass spectrometry. The most obvious particularity of the neuronal IR is because of alternative splicing, which results in two isoforms. Isoform A of the IR (IR-A), which lacks exon 11 (Fig. 1), predominates in the embryo and is the only isoform detectable in adult neurons, while IR-B, which includes exon 11, constitutes > 90% of total IR in the adult liver, adipose tissue and glia; the skeletal muscle contains comparable amounts of IR-A and IR-B (Joost 1995; Kenner et al. 1995; Garwood et al. 2015). The two isoforms, when present in the same cell type, display different insulin binding kinetics (Knudsen et al. 2011), and downstream effects (Leibiger et al. 2001). In a cell line model, IR-A and IR-B have been reported to reside in distinct membrane microdomains (Uhles et al. 2003). However, splicing alone cannot entirely explain the molecular behavior of the neuronal IR. The IR in peripheral tissues shows negative cooperativity: the binding of a second insulin molecule to the receptor dimer tends to dissociate the first one, limiting the mitogenic potential of insulin (Belfiore et al. 2009). The brain IR does not show negative cooperativity, even though IR-A homodimers in other tissues do (Joost 1995; De Meyts 2015). As regards particularities of the neuronal IR itself (Fig. 1), both its a and b chains are less highly glycosylated than in other tissues and in glia (Lowe et al. 1986; Brennan 1988; McElduff et al. 1988). Insofar as the different cooperativity of binding and downstream signaling of the brain IR result from properties of the IR itself, they may be correlated with the specific, developmentally regulated reduction in the IR sialic acid content in neurons (Brennan 1988); in nonneuronal cells, it has been shown that the insulin bindinginduced desialylation of the IR regulates IR activation (Dridi et al. 2013; Alghamdi et al. 2014).

Subcellular localization of neuronal IR signaling Immunocytochemical methods on cell fractions, cultured neurons and fixed tissue have shown the presence of the IR on the neuronal plasma membrane, and specifically on preand post-synaptic membranes (Weyhenmeyer et al. 1985; Marks et al. 1988; Abbott et al. 1999; De Felice et al. 2009; Zhao et al. 2009). Effects of the IR on downstream signaling are clearer in synaptic membrane fractions than in whole tissue lysates (Zhao et al. 1999; Dou et al. 2005), but as yet, little is known about the underlying dynamics of synaptic insulin action (Fig. 1). Data from adipocytes show that IR signaling is critically dependent on association with caveolae, and increased mobility of the IR in a complex with the ganglioside GM3 mediates the state of insulin resistance (Kabayama et al. 2007). Likewise, in cortical neurons, only the IR localized outside of ganglioside GM1 rafts responds to insulin; the raft-localized IR does not, apparently because of


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high tyrosine phosphatase activity in the rafts (Taghibiglou et al. 2009). In hypothalamic neurons, the inhibition of ganglioside synthesis makes the IR more responsive to insulin (Herzer et al. 2015). These results are very interesting, since the lipid composition of dendritic spines, especially the proportion of cholesterol and sphingolipids, differs from that of other neuronal membranes and modifies the activity of synaptic receptors including the IR (Dotti et al. 2014; Sallam et al. 2015). In spite of the high and growing interest in the function of the neuronal IR, no study on subsynaptic localization, conformational changes or mobility of the IR has been done in living neurons, much less in the synaptic terminals and dendritic spines where the IR is present and is poised to influence plasticity. The lack of such studies is even more surprising given the clear effects of IR activation on GABAAR, NMDAR and AMPAR (Wan et al. 1997; Skeberdis et al. 2001; Huang et al. 2004), all of which do display subsynaptic variation in mobility, activation kinetics or affinity: the endocytosis and exocytosis of GABAAR is spatially separated from its synaptic site of action (Bogdanov et al. 2006); synaptic and extra-synaptic NMDAR show distinct activation thresholds, which is not explained by subunit composition (Harris and Pettit 2007); the size of synaptic nanodomains containing AMPAR regulates synaptic transmission efficiency (Nair et al. 2013) (Fig. 1). IR downstream signaling may also vary within neurons because of the availability of downstream signaling partners. For example, another neuronal protein that has been shown, in vitro and in cell lines, to be phosphorylated in response to insulin (but not insulin-like growth factor 1, IGF-1) signaling is IRSp53 (Yeh et al. 1996; Okamura-Oho et al. 2001; Hori et al. 2005; Heung et al. 2008). IRSp53 is highly concentrated in post-synaptic densities (Abbott et al. 1999; Choi et al. 2005) and the only post-synaptic density protein found to be consistently and significantly down-regulated in Alzheimer’s disease (Zhou et al. 2013); furthermore, IRSp53 mutant mice have deficits in memory and social communication caused by excessive NMDAR and metabotropic glutamate signaling (Kim et al. 2009; Sawallisch et al. 2009; Chung et al. 2015; Bobsin and Kreienkamp 2016). These data make IRSp53, in principle, a very interesting candidate for post-synaptic density-specific insulin signaling. However, to the contrary of what has been shown for its peripheral homolog insulin receptor tyrosine kinase substrate (IRTKS) (Huang et al. 2013), it remains to be seen if IR and IRSp53 indeed modify each other in intact neurons, and if such a mutual interaction has functional consequences.

might be triggered not only by its binding to the IR, but also to the IGF-1 receptor (IGF-1R), and that the IR might be activated by insulin-like growth factors 1 or 2. In fact, IR-A, the isoform present in neurons, can be activated, in cell lines, by insulin-like growth factor 2, although at lower affinity than by insulin (Belfiore et al. 2009; Morcavallo et al. 2012). Whole tissue rat hippocampus insulin concentration is ~ 9 pM (Gomes et al. 2009), interstitial fluid insulin concentration in mouse hippocampus is ~ 10 pM (Stanley et al. 2016), and human cerebrospinal fluid concentration ~ 7 pM (Born et al. 2002), within the range of activation of the homodimeric IR and possibly of hybrid receptors (Li et al. 2005; Belfiore et al. 2009). However, even if the unknown synaptic cleft concentration of insulin is somewhat higher, it is almost certainly not high enough to activate homodimeric IGF1R (Belfiore et al. 2009). On the other hand, even though brain IGF-1 is largely produced in the brain (Ashpole et al. 2015) and IGF-1 brain concentrations are higher than for insulin (~ 160 pM in whole tissue rat hippocampus (Gomes et al. 2009) and ~ 400 pM in human cerebrospinal fluid (Pulford and Ishii 2001), these concentrations of IGF-1 are still much too low to activate the homodimeric IR (Belfiore et al. 2009). More insulin may be bound to hybrid receptors than to the IR in very early embryonic retina (Garcıa-De Lacoba et al. 1999). Since neuronal-specific IR knock-out mice have no defects in cognition nor in general neuronal development (Bruning et al. 2000; Schubert et al. 2004), while even partial neuronal-specific IGF-1R knock-out mice have severe brain development problems (Kappeler et al. 2008), this is an important question. In fact, it has been proposed that signaling through the neuronal IR largely regulates satiety and peripheral metabolism and does so through PI3Kdependent signaling, while insulin acting through IR/IGF-1R hybrid dimers and ERK is responsible for cognitive effects (Schubert et al. 2004; Bedinger and Adams 2015). However, there are reasons to affirm the relevance of the activation of the homodimeric IR by insulin for cognition. While no data from clinical interventions is available for tissue concentrations, insulin in human cerebrospinal fluid rises from ~ 7 pM before intervention to ~ 20 pM upon intranasal application (Born et al. 2002), and such an intervention is correlated with protection against cognitive loss in some patients (Claxton et al. 2013; H€ olscher 2014). Over this entire range, at least in endothelial cells, insulin activates IR much better than it does any other receptor (Li et al. 2005). Furthermore, in vitro studies have also produced evidence that supports cognitive effects through the IR without involvement of IGF-1R, using pharmacological manipulation (O’Malley et al. 2003; Lee et al. 2005).

Contributions of insulin-like growth factors and IGF-1R

Outlook

A problem when evaluating the importance of the IR for cognition is that the cognitive effects assigned to insulin

Exciting whole-organism results on the importance of the IR for synaptic plasticity and in the development of dementias



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Figure 1 Synaptic environment of the insulin receptor (IR) and its downstream signaling. Box: Each protomer of the IR contains a transmembrane b chain (blue and orange, respectively) and an extracellular a chain (turquoise; the other a chain is hidden). In contrast with other cell types, the neuronal IRs lack exon 11 and have lower sialylation. The intracellular domain contains both (self-) activating (tyrosine) and inhibitory (serine and threonine) phosphorylation sites, the complete set of which has not been determined in neurons. Synaptic terminal: In several model systems, binding of insulin (red spheres) to a receptor increases the release of noradrenaline (NE) and dopamine (Sauter et al. 1983) and inhibits the uptake of noradrenaline (Boyd et al. 1985); signaling of insulin through the IR increases dopaminergic firing frequency (Könner et al. 2011) and decreases dopamine degradation (Kleinridders et al. 2015). It is not clear which of these effects are cell autonomous and require a pre-synaptic insulin receptor. Dendritic spine: The IR may be present within or outside lipid rafts or associated with the post-synaptic density (PSD), or it may

undergo endocytosis, especially after binding insulin. The environment of each IR may determine if downstream signaling proceeds through Shc (Src homology 2 domain containing) and extracellular signalregulated kinases (ERK); or through the IR substrate (IRS) family and phosphatidylinositol-3-kinase (PI3K); or possibly through synapsespecific molecules, such as IRSp53. Downstream effects of hippocampal post-synaptic insulin signaling have been described to include inhibition of Ca2+ oscillations, mediated by ERK activation and K+ influx (O’Malley et al. 2003); depolarization because of enhanced exocytosis of NMDAR (Skeberdis et al. 2001); long-term depression as a result of exocytosis of GluA1- and endocytosis of GluA2-containing AMPAR (aamino-3-hydroxy-5-methylisoxazole-4-propionate receptor) (Passafaro et al. 2001); reduced excitability because of enhanced exocytosis of GABAAR (Jin et al. 2011); and increased spine formation or survival, mediated by PI3K activation (Lee et al. 2011). Some of these effects were observed using very high insulin concentrations.

have garnered the IR the attention of neuroscientists and driven a profusion of work on the brain IR. Very recent results have advanced our understanding of the importance of the brain IR, but the evident heterogeneity in patient response to insulin-based treatment, the discrepancies between acute and chronic models of IR deficiency, and the disagreement about the most important synaptic signaling pathways show that we still lack critical pieces of the puzzle (Schubert et al. 2004; Kleinridders et al. 2014; Bedinger and Adams 2015; Claxton et al. 2015; Grillo et al. 2015; Gejl et al. 2016; Stoeckel et al. 2016). An understanding of the dynamics of the synaptic IR, leveraging knowledge about the molecular

differences between the neuronal and peripheral IR, might help to place the cellular and whole-organism results on a more solid footing and rationalize the best ways to move forward in alleviating the heavy burden of brain diseases, especially Alzheimer’s dementia.

Acknowledgments and conflict of interest disclosure The author thanks Drs. Jose Henrique Ledo and Mychael V. Lourencßo and two anonymous reviewers for suggesting important improvements to this review. I acknowledge the support of Dr. Paul


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de Koninck and the Centre de Recherche du Institut Universitaire de la Sante Mentale du Quebec during the last phase of writing. No funding was received for the line of work described here. The author has no conflict of interest to declare.

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