Research Spotlights

DISRUPTION OF EXCITABLE AXONAL DOMAINS IN NEUROLOGICAL DISEASES

Dec 3, 2018

In healthy subjects, the excitable axonal domains known as the axon initial segment (AIS) and node of Ranvier (node) allow rapid, efficient, and regulated communication within the nervous system. Emerging evidence indicates that subtle disruption and/or plasticity of the structure-function relationship at these domains impairs neuronal function and is associated with a wide variety of neurological diseases. For example, Leo Yermakov, a MD/PhD candidate in the Susuki lab, recently published that type 2 diabetes leads to disruption of the AIS in the prefrontal cortex and hippocampal brain regions of mice [1]. Our current goal is to determine how excitable axonal domains are disrupted in type 2 diabetes and whether this leads to maladaptive neuronal network function and impairment of cognitive behavior. A clue comes from a recent publication from Dr. Ryan Griggs, a postdoctoral researcher in the lab, which reports that the diabetes-related metabolite methylglyoxal may disrupt nodes via the calcium-dependent protease calpain [2]. These publications form the basis of our current working hypothesis that activation of calpains by pathological elevation of methylglyoxal leads to disruption of both excitable axonal domains and brain function in diabetes and related neurodegenerative conditions.

[1] https://www.frontiersin.org/articles/10.3389/fncel.2018.00146/full

[2] https://journals.sagepub.com/doi/10.1177/1759091418766175

Inactivation of TRPM7 kinase in mice results in enlarged spleens, reduced T-cell proliferation and diminished store-operated calcium entry.

May 4, 2018

Abstract

T lymphocytes enlarge (blast) and proliferate in response to antigens in a multistep program that involves obligatory cytosolic calcium elevations. Store-operated calcium entry (SOCE) pathway is the primary source of Ca2+ in these cells. Here, we describe a novel modulator of blastogenesis, proliferation and SOCE: the TRPM7 channel kinase. TRPM7 kinase-dead (KD) K1646R knock-in mice exhibited splenomegaly and impaired blastogenic responses elicited by PMA/ionomycin or anti-CD3/CD28 antibodies. Splenic T-cell proliferation in vitro was weaker in the mutant compared to wildtype littermates. TRPM7 current magnitudes in WT and KD mouse T cells were, however, similar. We tested the dependence of T-cell proliferation on external Ca2+ and Mg2+ concentrations. At a fixed [Mg2+o] of ~0.4 mM, Ca2+o stimulated proliferation with a steep concentration dependence and vice versa, at a fixed [Ca2+o] of ~0.4 mM, Mg2+o positively regulated proliferation but with a shallower dependence. Proliferation was significantly lower in KD mouse than in wildtype at all Ca2+ and Mg2+ concentrations. Ca2+ elevations elicited by anti-CD3 antibody were diminished in KD mutant T cells and SOCE measured in activated KD splenocytes was reduced. These results demonstrate that a functional TRPM7 kinase supports robust SOCE, blastogenesis and proliferation, whereas its inactivation suppresses these cellular events.

DOI: 10.1038/s41598-018-21004-w

L290P/V mutations increase ERK3's cytoplasmic localization and migration/invasion-promoting capability in cancer cells.

Dec 12, 2017

$Image of Weiwen Long Ph.D.$

Abstract

Protein kinases are frequently mutated in human cancers, which leads to altered signaling pathways and contributes to tumor growth and progression. ERK3 is an atypical mitogen-activated protein kinase (MAPK) containing an S-E-G activation motif rather than the conserved T-X-Y motif in conventional MAPKs such as ERK1/2. Recent studies have revealed important roles for ERK3 in cancers. ERK3 promotes cancer cell migration/invasion and tumor metastasis, and its expression is upregulated in multiple cancers. Little is known, however, regarding ERK3 mutations in cancers. In the present study, we functionally and mechanistically characterized ERK3 L290P/V mutations, which are located within ERK3's kinase domain, and are shown to exist in several cancers including lung cancer and colon cancer. We found that in comparison with wild type ERK3, both L290P and L290V mutants have greatly increased activity in promoting cancer cell migration and invasion, but have little impact on ERK3's role in cell proliferation. Mechanistically, while they have no clear effect on kinase activity, L290P/V mutations enhance ERK3's cytoplasmic localization by increasing the interaction with the nuclear export factor CRM1. Our findings suggest that L290P/V mutations of ERK3 may confer increased invasiveness to cancers..

DOI: 10.1038/s41598-017-15135-9

SK channel inhibition mediates the initiation and amplitude modulation of synchronized burst firing in the spinal cord

Apr 4, 2017

$Ph.D. Candidate Amr Mahrous$

Abstract

Burst firing in motoneurons represents the basis for generating meaningful movements. Neuromodulators and inhibitory receptor blockers cocktails have been used for years to induce burst firing in vitro; however, the ionic mechanisms in the motoneuron membrane which contribute to burst initiation and amplitude modulation are not fully understood. Small conductance Ca2+-activated potassium channels (SK channels) regulate excitatory inputs and firing output of motoneurons and interneurons and, therefore, are a candidate for mediating bursting behavior. The present study examines the role of SK channels in the generation of synchronized bursting using an in vitro spinal cord preparation from adult mice. Our results show that SK channel inhibition is required for both initiation and amplitude modulation of burst firing. Specifically, administration of the synaptic inhibition blockers strychnine and picrotoxin amplified the spinal circuit excitatory drive but not enough to evoke bursting. However, when SK channels were inhibited using various approaches, the excitatory drive was further amplified and synchronized bursting was always evoked. Also, graded SK channel inhibition modulated the amplitude of the burst in a dose-dependent manner, which was reversed using SK channel activators. Importantly, modulation of neuronal excitability using multiple approaches failed to mimic the effects of SK modulators, suggesting a specific role for SK channel inhibition in generating bursting. Both NMDA and AMPA receptors were found to drive the synchronized bursts. Blocking gap junctions did not disturb the burst synchrony. These results demonstrate a novel mechanistic role for SK channels in initiating and modulating burst firing of spinal motoneurons.

https://www.ncbi.nlm.nih.gov/pubmed/28356481

J Neurophysiol. 2017 Mar 29:jn.00929.2016. doi: 10.1152/jn.00929.2016. [Epub ahead of print]

Biomedical Sciences Ph.D. Program

Biomedical Sciences Ph.D. Program

Research Spotlights

DISRUPTION OF EXCITABLE AXONAL DOMAINS IN NEUROLOGICAL DISEASES

Inactivation of TRPM7 kinase in mice results in enlarged spleens, reduced T-cell proliferation and diminished store-operated calcium entry.

L290P/V mutations increase ERK3's cytoplasmic localization and migration/invasion-promoting capability in cancer cells.

Abstract

SK channel inhibition mediates the initiation and amplitude modulation of synchronized burst firing in the spinal cord

Abstract

https://www.ncbi.nlm.nih.gov/pubmed/28356481

Biomedical Sciences Ph.D. Program

Science and Mathematics, College of

CoSM Departments

About COSM

About Wright State

Academics

Information For

Resources

Services