Gq-mER signaling has opposite effects on hypothalamic orexigenic and anorexigenic neurons.

Two populations of cells within the hypothalamus exert opposite actions on food intake: proopiomelanocortin (POMC) neurons decrease it, while neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase it. 17ß-Estradiol (E2) is a potent anorexigenic hormone that exerts both genomic and non-genomic, rapid actions on these metabolic neurons. This review focuses on the rapid membrane effects of E2 in both POMC and NPY/AgRP neurons and how these combined effects mediate the anorexigenic effects of this steroid.

The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17ß-estradiol.

Besides its quintessential role in reproduction, 17ß-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K(+) channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110ß subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.

Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons.

Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 ± 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 µM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 ± 6.9% and 42.0 ± 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m-chlorophenylpiperazine attenuated the M-current by 42.4 ± 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS-102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake.

Multicenter evaluation of electrical stimulation systems for walking.

OBJECTIVE: To test the long-term benefits of several noninvasive systems for functional electrical stimulation (FES) during walking. DESIGN: Forty subjects (average years since injury, 5.4) were studied in four centers for an average time of 1 year. Gait parameters were tested for all subjects with and without FES. Thus, subjects served as their own controls, since the specific effect of using FES could be separated from improvements resulting from other factors (e.g., training). SETTING: Subjects used the devices in the community, but were tested in a university or hospital setting. PATIENTS: Subjects with spinal cord injury (n = 31) were compared to subjects with cerebral damage (n = 9). MAIN OUTCOME MEASURES: Gait parameters (speed, cycle time, stride length). Acceptance was studied by means of a questionnaire. RESULTS: Some initial improvement in walking speed (average increase of >20%) occurred, and continuing gains were seen (average total improvement, 45%). The largest relative gains were seen in the slowest walkers (speeds of <0.3 m/sec). Acceptance of the FES systems was good and improved systems have been developed using feedback from the subjects. CONCLUSIONS: Based on the improvements in speed and the acceptance of these FES systems, a greatly increased role for FES in treating gait disorders is suggested.

Immune response to Acinetobacter calcoaceticus infection in man.

After growth in an iron-depleted chemically-defined medium Acinetobacter calcoaceticus expressed four high mol. wt outer-membrane proteins (OMPs) which were repressed under iron supplementation or in a complex laboratory medium. Immunoblotting with serum from a septicaemic patient infected with A. calcoaceticus revealed antibody binding to these iron-repressible OMPs, indicating that they were expressed in vivo, and also to the 42- and 18-Kda OMPs. Although the antibody response to the OMPs did not vary significantly during convalescence, the response to the O-polysaccharide component of lipopolysaccharide decreased significantly. However, antibodies in serum from patients with A. calcoaceticus wound infections reacted with the iron repressible OMPs and a 54-Kda antigen suggesting a difference in immune recognition between local and systemic infection.