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Molecular basis for the
upregulation of neuronal nicotinic receptors.
Our more recent project relates
to the nicotine-induced upregulation of neuronal nicotinic receptors.
HIV-1 gp120-induced
upregulation of the
a7AChR in human macrophages at
nM concentrations (B and C).
Control experiment is shown in A.
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Neuronal nicotinic
receptors (nAChRs) are involved in a range of cerebral functions including
attention, learning, and memory. A loss of nAChR subunits is associated with
diseases such as Alzheimer’s disease (AD), dementia with Lewis bodies (DLB),
Parkinson’s disease and schizophrenia. Chronic nicotine exposure in tobacco
smokers and experimental animals produces an increase in brain binding sites for
nicotine. This increase in the number of nAChRs is commonly known as “upregulation”.
Specifically, chronic nicotine administration induces the up-regulation of
mammalian a4b2 neuronal nAChR in the central nervous system (CNS). Another study
from our laboratory demonstrated that the upregulation of the a4b2-AChR induced
by chronic nicotine exposure depends on the subunit stoichiometry
Lopez-Hernandez et al., 2004). Other nAChR subtypes may also be upregulated
but only at higher concentrations of nicotine. The unexpected “upregulation” of
nAChRs is probably a response to desensitization of the receptor by chronic
nicotine exposure. Recently we found that chronic exposure to a treatment
combining HIV-gp120 (15 nM), nicotine (500 nM) and galantamine (500 nM) produces
a remarkable upregulation (11-fold) of the a7 nAChR in human macrophages in
vitro (Santiago et al., 2006). Moreover, a 15 nanomolar concentration of gp120
alone induced a substantial upregulation (5-fold) of the a7 nAChR in human
macrophages. The upregulation of the a4b2 and a7 nAChR is extremely relevant to
nicotine tolerance and dependence. The goal of these studies is to gain insight
into the molecular mechanisms of upregulation of two neuronal nicotinic
receptors types. The gp120-induced upregulation of the a7 nAChR has just been
found in human macrophage; therefore, this is a new research project of this
laboratory. The upregulation of the a7 nAChR induced by HIV-gp120 could have
serious implications in processes ranging from neurodegeneration to inflammation
in HIV-infected patients. We hypothesize that the mechanisms involved in the
upregulation of nAChRs are diverse and structure-dependent. The study of two
different nAChRs will further understanding the molecular mechanisms governing
upregulation of these receptors from a structural and functional perspective.
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