Somatostatin (somatotrophin release-inhibiting factor, SRIF), a fourteen amino acid peptide, was discovered in the hypothalamus (Brazeau et al. 1973). This peptide was shown to inhibit the secretion of growth hormone in the hypophysis (Brazeau et al. 1973). Later, SRIF was shown to be widely distributed in the brain, and it is now known to be an important neurotransmitter in the brain. The locus coeruleus, a pair of small nuclei located in the brainstem, consists of tightly packed noradrenergic neurones which project to virtually the entire brain and spinal cord. Hence, this nucleus, as the main supplier of noradrenaline in the brain, plays a vital role in brain function. SRIF inhibits locus coeruleus neurones by activating an inward rectifier K¤ current, and this SRIF effect is mediated through a pertussis toxin (PTX)-sensitive G protein (Inoue, Nakajima & Nakajima, 1988). However, the type (or types) of PTX-sensitive G protein (Gi1, Gi2, Gi3 or Gï) involved in this SRIF effect has yet to be determined. In AtT-20 cells (a mouse pituitary tumour cell line) and in human pituitary tumour cells, SRIF activates an inward rectifier K¤ current, and this SRIF effect is also mediated by a PTX-sensitive G protein (Yamashita, Shibuya & Ogata, 1988;Pennefather, Heisler & MacDonald, 1988;Kozasa, Kaziro, Ohtsuka, Grigg, Nakajima & Nakajima, 1996). In AtT-20 cells as well, it has not yet been determined which one of several PTX-sensitive G proteins is involved in the SRIF effect. The objective of this paper is to identify the G protein that mediates the SRIF effect on inward rectifier K¤ currents in locus coeruleus neurones and in 1. Types of G proteins (G protein á_subunit subtypes) which mediate the activation of inward rectifier K¤ currents by somatostatin (somatotrophin release-inhibiting factor, SRIF) were determined in cultured locus coeruleus neurones from newborn rats and in AtT-20 cells (a mouse pituitary cell line). 2. The whole-cell patch clamp technique was used together with injection of antibodies against pertussis toxin (PTX)-sensitive G protein á_subunits or with injection of antisense (or sense) oligonucleotides against these G proteins. 3. In locus coeruleus neurones, the SRIF-induced activation of inward rectifier K¤ currents was inhibited by anti-Gái1ÏGái2 antibody injection, but not by anti-Gái3 or by anti-GáïÏGái3 antibody injection, suggesting that the SRIF response is mediated through Gái1 andÏor Gái2. 4. The SRIF-induced activation of the inward rectifier was suppressed in locus coeruleus neurones after injection of antisense oligonucleotides against Gái2, but not by injection of sense oligonucleotides against Gái2. Injection of antisense (or sense) oligonucleotides against Gái1, Gái3 and Gáï(common) had no effect. These results suggest that Gái2 is involved in this SRIF response. 5. In AtT-20 cells, the SRIF-induced activation of inward rectifier K¤ currents was suppressed by injection of anti-Gái3 antibody, but not by injection of anti-Gái1ÏGái2 antibody. 6. The above results indicate that Gé medi...