Growth factors regulate phototransduction in retinal rods by modulating cyclic nucleotide-gated channels through dephosphorylation of a specific tyrosine residue

Illumination of vertebrate rod photoreceptors leads to a decrease in the cy toplasmic cGMP concentration and closure of cyclic nucleotide-gated (CNC) c hannels. Except for Ca2+, which plays a negative feedback role in adaptatio n, and 11-cis-retinal, supplied by the retinal pigment epithelium, all of t he biochemical machinery of phototransduction is thought to be contained wi thin rod outer segments without involvement of extrinsic regulatory molecul es. Here we show that insulin-like growth factor-I (IGF-I), a paracrine fac tor released from the retinal pigment epithelium, alters phototransduction by rapidly increasing the cGMP sensitivity of CNG channels. The IGF-I-signa lling pathway ultimately involves a protein tyrosine phosphatase that catal yzes dephosphorylation of a specific residue in the cu-subunit of the rod C NG channel protein. IGF-I conjointly accelerates the kinetics and increases the amplitude of the light response, distinct from events that accompany a daptation. These effects of IGF-I could result from the enhancement of the cGMP sensitivity of CNC channels. Hence, in addition to long-term control o f development and survival of rods, growth factors regulate phototransducti on in the short term by modulating CNG channels.