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The rod pigment, rhodopsin, shows spontaneous isomerization activity. This quantal noise produces a dark light of approximately 0.01 photons s(-1) rod(-1) in human, setting the threshold for rod vision. The spontaneous isomerization activity of human cone pigments has long remained a mystery because the effect of a single isomerized pigment molecule in cones, unlike that in rods, is small and beyond measurement. We have now overcome this problem by expressing human red cone pigment transgenically in mouse rods in order to exploit their large single-photon response, especially after genetic removal of a key negative-feedback regulation. Extrapolating the measured quantal noise of transgenic cone pigment to native human red cones, we obtained a dark rate of approximately 10 false events s(-1) cone(-1), almost 10(3)-fold lower than the overall dark transduction noise previously reported in primate cones. Our measurements provide a rationale for why mammalian red, green and blue cones have comparable sensitivities, unlike their amphibian counterparts.

An important mechanism by which vertebrate olfactory sensory neurons rapidly adapt to odorants is feedback modulation of the Ca(2+)-permeable cyclic nucleotide-gated (CNG) transduction channels. Extensive heterologous studies of homomeric CNGA2 channels have led to a molecular model of channel modulation based on the binding of calcium-calmodulin to a site on the cytoplasmic amino terminus of CNGA2. Native rat olfactory CNG channels, however, are heteromeric complexes of three homologous but distinct subunits. Notably, in heteromeric channels, we found no role for CNGA2 in feedback modulation. Instead, an IQ-type calmodulin-binding site on CNGB1b and a similar but previously unidentified site on CNGA4 are necessary and sufficient. These sites seem to confer binding of Ca(2+)-free calmodulin (apocalmodulin), which is then poised to trigger inhibition of native channels in the presence of Ca(2+).

All cellular signaling pathways currently known to elevate cGMP involve the activation of a guanylyl cyclase to synthesize cGMP. Here we describe an exception to this rule. In the vertebrate parietal eye, the photoreceptors depolarize to light under dark-adapted conditions, unlike rods and cones but like most invertebrate photoreceptors. We report that the signaling pathway for this response involves a rise in intracellular cGMP resulting from an inhibition of the phosphodiesterase that hydrolyzes cGMP. Furthermore, this phosphodiesterase is driven by an active G protein in darkness. These results indicate an antagonistic control of the phosphodiesterase by two G proteins, analogous to the Gs/Gi control of adenylyl cyclase. Our findings demonstrate an unusual phototransduction mechanism and at the same time indicate that signaling involving cyclic nucleotides is more elaborate than previously known.