Diabetes, a disease in which carbohydrate and lipid metabolism are regulated improperly by insulin, is a serious worldwide health issue. Insulin is secreted from pancreatic beta cells in response to elevated plasma glucose, with various factors modifying its secretion. Free fatty acids (FFAs) provide an important energy source as nutrients, and they also act as signalling molecules in various cellular processes, including insulin secretion. Although FFAs are thought to promote insulin secretion in an acute phase, this mechanism is not clearly understood. Here we show that a G-protein-coupled receptor, GPR40, which is abundantly expressed in the pancreas, functions as a receptor for long-chain FFAs. Furthermore, we show that long-chain FFAs amplify glucose-stimulated insulin secretion from pancreatic beta cells by activating GPR40. Our results indicate that GPR40 agonists and/or antagonists show potential for the development of new anti-diabetic drugs.

The C. elegans tax-4 mutants are abnormal in multiple sensory behaviors: they fail to respond to temperature or to water-soluble or volatile chemical attractants. We show that the predicted tax-4 gene product is highly homologous to vertebrate cyclic nucleotide-gated channels. Tax-4 protein expressed in cultured cells functions as a cyclic nucleotide-gated channel. The green fluorescent protein (GFP)-tagged functional Tax-4 protein is expressed in thermosensory, gustatory, and olfactory neurons mediating all the sensory behaviors affected by the tax-4 mutations. The Tax-4::GFP fusion is partly localized at the sensory endings of these neurons. The results suggest that a cyclic nucleotide-gated channel is required for thermosensation and chemosensation and that cGMP is an important intracellular messenger in C. elegans sensory transduction.

We searched for peptidic ligands for orphan G protein-coupled receptors utilizing a human genome data base and identified a new gene encoding a preproprotein that could generate a peptide. This peptide consisted of 43 amino acid residues starting from Nterminal pyroglutamic acid and ending at C-terminal arginine-phenylalanine-amide. We therefore named it QRFP after pyroglutamylated arginine-phenylalanineamide peptide. We subsequently searched for its receptor and found that Chinese hamster ovary cells expressing an orphan G protein-coupled receptor, AQ27, specifically responded to QRFP. We analyzed tissue distributions of QRFP and its receptor mRNAs in rats utilizing quantitative reverse transcription-polymerase chain reaction and in situ hybridization. QRFP mRNA was highly expressed in the hypothalamus, whereas its receptor mRNA was highly expressed in the adrenal gland. The intravenous administration of QRFP caused the release of aldosterone, suggesting that QRFP and its receptor have a regulatory function in the rat adrenal gland.

Serotonin (5-HT) modulates synaptic efficacy in the nervous system of vertebrates and invertebrates. In the nematode Caenorhabditis elegans, many behaviors are regulated by 5-HT levels, which are in turn regulated by the presence or absence of food. Here, we show that both food and 5-HT signaling modulate chemosensory avoidance response of octanol in C. elegans, and that this modulation is both rapid and reversible. Sensitivity to octanol is decreased when animals are off food or when 5-HT levels are decreased; conversely, sensitivity is increased when animals are on food or have increased 5-HT signaling. Laser microsurgery and behavioral experiments reveal that sensory input from different subsets of octanol-sensing neurons is selectively used, depending on stimulus strength, feeding status, and 5-HT levels. 5-HT directly targets at least one pair of sensory neurons, and 5-HT signaling requires the G␣ protein GPA-11. Glutamatergic signaling is required for response to octanol, and the GLR-1 glutamate receptor plays an important role in behavioral response off food but not on food. Our results demonstrate that 5-HT modulation of neuronal activity via G protein signaling underlies behavioral plasticity by rapidly altering the functional circuitry of a chemosensory circuit.A t the level of individual synapses, plasticity usually refers to changes in efficacy of synaptic transmission. However, at the scale of a neural network, this plasticity translates to changes in functional circuitry. The 302 neurons of the Caenorhabditis elegans nervous system are largely invariant in their location and lineage, and the overall pattern of synaptic connections between classes of neurons is similar in multiple animals (1). With limited variability in synaptic connectivity, behavioral plasticity in C. elegans likely occurs by differential utilization of existing synaptic connections, rather than de novo synaptogenesis.The biogenic amine serotonin (5-HT) modulates synaptic efficacy in vertebrates and invertebrates. For example, 5-HT modulates both locomotor reflex and nociception in the rat spinal cord (2, 3). In cultured Aplysia neurons 5-HT is critical for both short-term and long-term changes in synaptic efficacy (4, 5). In humans, defects in 5-HT signaling are implicated in behavioral disorders, including depression, bulimia, obsessivecompulsive disorder, and alcoholism (6). Although drugs that increase synaptic 5-HT levels such as fluoxetine (i.e., Prozac) are often used to treat these conditions, very little is known about how altering 5-HT levels causes changes in functional circuitry or behavior.Several lines of evidence suggest that in C. elegans, high levels of 5-HT signal the presence of food. In the presence of food (Escherichia coli is used as a food source in the laboratory), pharyngeal pumping (7, 8), egg laying (8, 9), and male mating (10) are increased, whereas locomotion is decreased (11). Conversely, in the absence of food, the opposite behaviors are observed. The effect of food on these behaviors can largely be...