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Biomedical subjects

Lorise C Gahring

Publications and source records attributed to Lorise C Gahring.

10 recordsLinked to original sources

Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells.

Of the thousands of proven carcinogens and toxic agents contained within a cigarette, nicotine, while being the addictive agent, is often viewed as the least harmful of these compounds. Nicotine is a lipophilic molecule whose effects on neuronal nicotinic acetylcholine receptors (nAChR) have been primarily focused on its physiologic impact within the confines of the brain and peripheral nervous system. However, recently, many studies have found neuronal nAChRs to be expressed on many different nonneuronal cell types throughout the body, where increasing evidence suggests they have important roles in determining the consequences of nicotine use on multiple organs systems and diseases as diverse as ulcerative colitis, chronic pulmonary obstructive disease, and diabetes, as well as the neurologic disorders of Parkinson's and Alzheimer's disease. This review highlights current evidence for the expression of peripheral nAChRs in cells other than neurons and how they participate in fundamental processes, such as inflammation. Understanding these processes may offer novel therapeutic strategies to approach inflammatory diseases, as well as precautions in the design of interventional drugs.

Animals↗

Age-related loss of neuronal nicotinic receptor expression in the aging mouse hippocampus corresponds with cyclooxygenase-2 and PPAR gamma expression and is altered by long-term NS398 administration.

Age-related changes in the mammalian dorsal hippocampus are associated with diminished expression of neuronal nicotinic acetylcholine receptors (nAChR), which is particularly severe in pathologies such as those associated with dementias, including Alzheimer's disease. Because the mouse is a useful model for age-related decline in nAChR expression in the basal forebrain and limbic system, we used immunohistochemistry to examine the influence of long-term (12-month) oral administration of nicotine and/or the cyclooxygenase-2 (COX-2) preferring non-steroidal anti-inflammatory drug (NSAID) NS398 on nAChR alpha4, alpha5, alpha7, and beta4 expression in the C57BL/6 mouse. Inhibitory neurons of the dorsal hippocampus that express nAChRs also constitutively express COX-2 and the peroxisome proliferator-antagonist receptor subtype gamma-2 (PPAR gamma2) which is also a target of NS398. Administration of NS398 correlated with retention of nAChR alpha4 and to a lesser extent nAChR beta4, but not nAChR alpha5 or alpha7, but nicotine exhibited no similar effect. Nicotine and NS398 co-administration abolished the NS398-related effect on nAChR alpha4 retention. These results provide evidence that the interaction during aging between oral administration of nicotine and NSAIDs are not straightforward and could even be antagonistic when combined.

Aging↗

Pro-inflammatory cytokines modify neuronal nicotinic acetylcholine receptor assembly.

We have examined the impact of the inflammatory cytokines interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) on assembly of nAChRs from subunit mixtures of nAChRalpha4, beta2 and beta4 transiently transfected into 293 cells. In control transfections approximately 55% of alpha4 associated preferentially with beta4, but less than 15% complexed with beta2 and the remainder was associated with both beta subunits. These relative ratios were modified by pro-inflammatory cytokines. IL-1beta strongly enhanced alpha4/beta2 association and decreased alpha4/beta4, whereas TNFalpha promoted mixed alpha4/beta2/beta4 interactions. These results show that the emerging rules governing assembly of nAChRs are subject to modification by the pro-inflammatory cytokine environment.

Animals↗

Mouse strain-specific changes in nicotinic receptor expression with age.

The onset and severity of age-related loss of neuronal nicotinic acetylcholine receptor (nAChR) expression in the mammalian hippocampus can vary considerably between individuals. We have examined the expression of four nAChR subunits (nAChR alpha4, nAChR alpha5, nAChR alpha7 and nAChR beta4) in the dorsal hippocampus of adult (12-14 months) and aged (24-28 month) animals from two-mouse strains (CBA/J and C57BL/6). The expression of nAChR alpha4 was selectively diminished with age in both strains, and there was a significant loss of nAChR alpha7 in CA1 of aged CBA/J, but not C57BL/6. There was no change in nAChR alpha5 expression with age whereas nAChR beta4 preferentially diminished in the C57BL/6 CA1 region and remained the same or slightly increased in the aged CBA/J. Coincident with the loss of neuronal nAChR alpha4 in the CBA/J strain was a significant age-related increase of nAChR alpha4 staining of astrocytes, most notably in the stratum radiatum. These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChRs.

Aging↗

Neuronal and astrocyte expression of nicotinic receptor subunit beta4 in the adult mouse brain.

Neuronal nicotinic acetylcholine receptor (nAChR) expression and function are customized in different brain regions through assembling receptors from closely related but genetically distinct subunits. Immunohistochemical analysis of one of these subunits, nAChRbeta4, in the mouse brain suggests an extensive and potentially diverse role for this subunit in both excitatory and inhibitory neurotransmission. Prominent immunostaining included: 1) the medial habenula, efferents composing the fasciculus retroflexus, and the interpeduncular nucleus; 2) nuclei and ascending tracts of the auditory system inclusive of the medial geniculate; 3) the sensory cortex barrel field and cell bodies of the ventral thalamic nucleus; 4) olfactory-associated structures and the piriform cortex; and 5) sensory and motor trigeminal nuclei. In the hippocampus, nAChRbeta4 staining was limited to dendrites and soma of a subset of glutamic acid dehydrogenase-positive neurons. In C57BL/6 mice, but to a lesser extent in C3H/J, CBA/J, or CF1 mice, a subpopulation of astrocytes in the hippocampal CA1 region prominently expressed nAChRbeta4 (and nAChRalpha4). Collectively, these results suggest that the unique functional and pharmacological properties exerted by nAChRbeta4 on nAChR function could modify and specialize the development of strain-specific sensory and hippocampal-related characteristics of nicotine sensitivity including the development of tolerance.

Animals↗

Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus.

The response by individuals to nicotine is likely to reflect the interaction of this compound with target nAChRs. However, resolving how different genetic backgrounds contribute to unique mouse strain-specific responses to this compound remains an important and unresolved issue. To examine this question in detail, expression of the nicotine acetylcholine receptor (nAChR) subunits alpha3, alpha4, alpha5, alpha7, beta2, and beta4 was measured in the dorsal hippocampus using immunohistochemistry in mouse strains or lines BALB/c, C3H/J, C57BL/6, CBA/J, DBA/2, Long Sleep (LS), Short Sleep (SS), and CF1. The nAChRs in all mice colocalized with glutamic acid decarboxylase (GAD)-positive interneurons that were subclassified into at least four groups based on nAChR subunit heterogeneity. A notable difference between mouse strains was the expression of nAChRs by astrocyte subpopulations in CA1 subregions whose numbers vary inversely with nAChR-immunostained neurons. This novel relationship also correlated with published parameters of strain sensitivity to nicotine. Attempts to identify the origin of this significant difference in nAChR expression among strains included comparison of the entire nAChRalpha4 gene sequence. Although multiple polymorphisms were identified, including two that changed nAChRalpha4 amino acid coding, none of these clearly correlate with strain-related differences in cell type-specific nAChR expression. These findings suggest that mouse strain-specific behavioral and physiological responses to nicotine are likely to be a reflection of a complex interplay between genetic factors that shape differences in expression and cellular architecture of this modulatory neurotransmitter system in the mammalian nervous system.

Acetylcholine↗

Glutamate receptor subunit 3 is modified by site-specific limited proteolysis including cleavage by gamma-secretase.

Ionotropic glutamate receptor (GluR) expression and function is regulated through multiple pre- and post-translational mechanisms. We find that limited proteolytic cleavage of GluR3 at two distinct sites generates stable GluR3 short forms that are glycosylated and found in association with other full-length GluRs in the mouse brain and cultured primary neurons. A combination of mutagenesis and transfection into HEK293 cells revealed cleavage by a gamma-secretase-like activity within the membrane-localized re-entry loop at or near the leucine-glycine pair (amino acids 585-586, GluR3sbeta) and a second site within a proline-rich PEST-like sequence in the first cytoplasmic loop (Asp570-Pro571, GluR3salpha). Generation of the prominent GluR3salpha form was effectively abolished in the mutant, GluR3D570A, but inhibitors of lysosomes, the proteasome, caspases, or calpains had no effect. The possible impact of cleavage on receptor function was suggested when the co-expression of the GluR3P571Stop mutant (creating GluR3salpha) co-assembled with other GluR subunits and decreased receptor function in Xenopus oocytes. In transiently transfected HEK293 cells, co-expression of GluR3salpha alters the relative association between GluR1 and GluR3 during assembly, and the presence of the novel C-terminal proline-rich domain of GluR3salpha imparts lateral membrane mobility to GluR complexes. These results suggest that limited proteolysis is another post-translational mechanism through which functional diversity and specialization between closely related GluR subunits is accomplished.

Amyloid Precursor Protein Secretases↗

Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or beta-amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines.

Nicotine, the causative agent of addiction to tobacco, can also be a neuroprotectant. Nicotine-induced neuroprotection against different toxins is imparted through pharmacologically distinct neuronal nicotinic acetylcholine receptors (nAChR) where protection against chronic N-methyl-d-aspartic acid (NMDA) exposure is through nAChRalpha7 but protection against the toxic peptide of amyloid precursor protein, Abeta25-35, is through nAChRalpha4beta2. The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is also neuroprotective, however, in the presence of nicotine, neuroprotection against NMDA is abolished. The specificity of nicotine-TNFalpha antagonism was further refined using a mouse transgenic dominant negative of nAChRalpha7 in which nicotine failed to induce neuroprotection against NMDA and antagonism of TNFalpha was absent. However, nicotine-mediated neuroprotection against Abeta25-35 was unaffected and, therefore, did not require the expression of functional nAChRalpha7s. The mechanism of TNFalpha-mediated neuroprotection and antagonism by nicotine was independent of caspase 8 activation or nuclear factor kappa B translocation in neurons but C6-ceramide addition to neuronal cultures subsequently exposed to NMDA mimicked the neuroprotective effect of TNFalpha and, like TNFalpha, it was antagonized by cotreatment with nicotine. Therefore, the neuroprotective effects of nicotine against differing toxic assaults requires distinct nAChR subtypes and proceeds through intracellular pathways that overlap with similarly different mechanisms initiated by pro-inflammatory cytokines. These results provide insight into how nicotine imparts neuroprotection and modulates inflammatory responses.

Amyloid beta-Peptides↗

Autoimmunity to glutamate receptors in the central nervous system.

Autoimmunity to glutamate receptors (GluR) of the central nervous system offers an attractive model to begin the experimental dissection of the etiology of immune-related neurodegenerative diseases. Here we discuss the known mechanisms of generating autoimmunity to different members of the GluR neurotransmitter receptor family within the unique environment of the brain and how autoantibody-receptor interactions contribute to abnormal neurotransmission and eventually pathology.

Amino Acid Sequence↗

Nicotine preconditioning antagonizes activity-dependent caspase proteolysis of a glutamate receptor.

Neuronal excitation is required for normal brain function including processes of learning and memory, yet if this process becomes dysregulated there is reduced neurotransmission and possibly death through excitotoxicity. Nicotine, through interaction with neuronal nicotinic acetylcholine receptors, possesses the ability to modulate neurotransmitter systems through numerous mechanisms that define this critical balance. We examined the modulatory role of nicotine in primary mixed cortical neuronal-glial cultures on activity-dependent caspase cleavage of a glutamate receptor, GluR1. We find that GluR1, but not GluR2 or GluR3, is a substrate for agonist (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid)-initiated rapid proteolytic cleavage at aspartic acid 865 through the activation of caspase 8-like activity that is independent of membrane fusion and is not coincident with apoptosis. Dose-dependent nicotine preconditioning for 24 h antagonizes agonist-initiated caspase cleavage of GluR1 through a mechanism that is coincident with desensitization of both nAChRalpha4beta2 and nAChRalpha7 receptors and the delayed activation of a caspase 8-like activity. The modulation of GluR1 agonist-initiated caspase-mediated cleavage by nicotine preconditioning offers a novel insight into how this agent can impart its numerous effects on the nervous system.

Animals↗