Nerve Growth Factor Receptor TrkA, a New Receptor in Insulin Signaling Pathway in PC12 Cells

Geetha, Thangiah; Rege, Shraddha D.; Mathews, Salome E.; Meakin, Susan O.; White, Morris F.; Babu, Jeganathan Ramesh

doi:10.1074/jbc.m112.436279

Cited by 27 publications

(21 citation statements)

References 39 publications

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“…In addition, we found differential expression of the InsR in PSNs innervating somatic and visceral organs, respectively. In PC12 cells, which share characteristics with nociceptive PSNs, the InsR has recently been shown to form a complex with TrkA, the receptor activated by NGF (Geetha et al 2013). NGF is essential in the development of functional traits and neurochemical phenotypes of nociceptive PSNs (Snider and McMahon 1998).…”

Section: Discussionmentioning

confidence: 99%

The insulin receptor is differentially expressed in somatic and visceral primary sensory neurons

et al. 2018

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Recent studies demonstrated the expression of the insulin receptor (InsR) and its functional interaction with the transient receptor potential vanilloid type 1 receptor (TRPV1) in primary sensory neurons (PSNs). The present study was undertaken to reveal the target-specific expression of the InsR and its co-localization with the TRPV1 in rat PSNs. We assessed the localization of the InsR and its co-localization with the TRPV1 in PSNs retrogradely labelled with biotin-conjugated wheat germ agglutinin injected into the dorsal hind paw skin, the gastrocnemius muscle, the pancreas and the urinary bladder wall. The largest proportions of retrogradely labelled InsR-immunoreactive neurons were identified among PSNs serving the pancreas (~ 54%) and the urinary bladder (~ 53%). The proportions of retrogradely labelled InsR-immunoreactive neurons innervating the dorsal hind paw skin and the gastrocnemius muscle amounted to ~ 22 and ~ 21%. TRPV1-immunoreactive neurons amounted to ~ 63, ~ 62, ~ 67 and ~ 65% of retrogradely labelled cutaneous, muscle, pancreatic and urinary bladder PSNs, respectively. Co-localization of the TRPV1 with the InsR was observed in ~ 16, ~ 15, ~ 29 and ~ 30% of retrogradely labelled cutaneous, muscle, pancreatic and urinary bladder PSNs. These quantitative immunohistochemical data demonstrate a preponderance of InsR-immunoreactivity among PSNs, which innervate visceral targets. The present findings suggest that visceral spinal PSNs are more likely to be exposed to the modulatory effects of insulin on sensory functions, including neurotrophic, nociceptive and inflammatory processes.

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Section: Discussionmentioning

confidence: 99%

The insulin receptor is differentially expressed in somatic and visceral primary sensory neurons

et al. 2018

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“…Although, these studies suggested a crucial role of the InsR in neurite growth, it has also been demonstrated that the InsR forms a molecular complex with the TrkA in PC12 cells which show similarities with nociceptive sensory neurons [143]. Further, it has been demonstrated that TrkA is involved in insulin signaling by regulating the MAPK or Akt cascades [143].…”

Section: Role Of Insulin and Insrs In Neurite Outgrowth And Regeneratmentioning

confidence: 99%

“…In contrast, spontaneous regeneration was inhibited by local application of an anti-IGF antiserum to the injured nerve [152]. Recent findings suggest that the neurotrophic effects of insulin and IGF-1, similarly to NGF, may be mediated through activation of TrkA [143]. TrkA is also involved in the development of the neurochemical phenotypes of nociceptive PSNs and, importantly, the expression of the TRPV1 receptor is regulated by NGF [77,153].…”

Section: Role Of Insulin and Insrs In Neurite Outgrowth And Regeneratmentioning

confidence: 99%

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Lázár

Jancsó

Stella

2020

IJMS

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Insulin, besides its pivotal role in energy metabolism, may also modulate neuronal processes through acting on insulin receptors (InsRs) expressed by neurons of both the central and the peripheral nervous system. Recently, the distribution and functional significance of InsRs localized on a subset of multifunctional primary sensory neurons (PSNs) have been revealed. Systematic investigations into the cellular electrophysiology, neurochemistry and morphological traits of InsR-expressing PSNs indicated complex functional interactions among specific ion channels, proteins and neuropeptides localized in these neurons. Quantitative immunohistochemical studies have revealed disparate localization of the InsRs in somatic and visceral PSNs with a dominance of InsR-positive neurons innervating visceral organs. These findings suggested that visceral spinal PSNs involved in nociceptive and inflammatory processes are more prone to the modulatory effects of insulin than somatic PSNs. Co-localization of the InsR and transient receptor potential vanilloid 1 (TRPV1) receptor with vasoactive neuropeptides calcitonin gene-related peptide and substance P bears of crucial importance in the pathogenesis of inflammatory pathologies affecting visceral organs, such as the pancreas and the urinary bladder. Recent studies have also revealed significant novel aspects of the neurotrophic propensities of insulin with respect to axonal growth, development and regeneration.

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“…[64][65] In comparison to other RTKs, TRK is most similar to the insulin receptor and has been implicated in insulin signaling. 67 Figure 1. Schematic view of TRK receptor tyrosine kinases and major signal transduction pathways involved in cell differentiation, proliferation, and survival.…”

Section: Trk Biology and Signalingmentioning

confidence: 99%

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

et al. 2018

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The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

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Nerve Growth Factor Receptor TrkA, a New Receptor in Insulin Signaling Pathway in PC12 Cells

Cited by 27 publications

References 39 publications

The insulin receptor is differentially expressed in somatic and visceral primary sensory neurons

The insulin receptor is differentially expressed in somatic and visceral primary sensory neurons

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

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