Somatostatin-14 (SRIF) and its receptors (sst(1-5)) are found in the mammalian retina. However, scarce information is available on the role of the somatostatinergic system in retinal physiology. We have recently used gene-knockout technology to gain insights into the function of sst(1) and sst(2) receptors in the mouse retina. The sst(1) receptor localizes to SRIF-containing amacrine cells, whereas the sst(2) receptor localizes to several retinal cell populations including rod bipolar cells (RBCs). Molecular data indicate that, in retinas with deletion of the sst(1) receptor (sst(1) KO), sst(2) receptors become overexpressed in concomitance with an increased level of retinal SRIF. To test whether this up-regulation of sst(2) receptors correlates with altered sst(2) receptor physiology, we studied the effect of sst(2) receptor activation on potassium current (I(K)) in isolated RBCs and glutamate release in retina explants. Both I(K) and glutamate release are known to be negatively modulated by sst(2) receptors in the mammalian retina. We used octreotide, a SRIF analogue, to activate selectively sst(2) receptors. Patch-clamp recordings from isolated RBCs indicated that the sst(2) receptor-mediated inhibition of I(K) was significantly larger in sst(1) KO than in control retinas. In addition, HPLC measurements of glutamate release in sst(1) KO retinal explants demonstrated that the sst(2) receptor-mediated inhibition of K(+)-evoked glutamate release was also significantly larger than in control retinas. As a whole, these findings indicate that the overexpression of sst(2) receptors in sst(1) KO retinas can be correlated to an enhanced function of sst(2) receptors. The level of expression of sst(2) receptors may therefore represent a key step in the regulation of sst(2) receptor-mediated responses, at least in the retina.