Neuropharmacology

Biography

Biography: Clint L. Makino

Abstract

In the first step of vision, retinal rods and cones capture light and generate an electrical response. Upon photoexcitation, the visual pigment activates a G protein coupled cascade that results in hydrolysis of the ROS-GC guanylate cyclase-generated cGMP, closure of cyclic nucleotide gated (CNG) cation channels and membrane hyperpolarization. To control the growth of the response and to speed up the recovery, there is a negative feedback loop based on free [Ca2+]. In darkness, Ca2+ enters the photoreceptor through the CNG channel. Channel closure by induced by light prevents Ca2+ entry, but continued extrusion by an exchanger causes the intracellular [Ca2+] to fall. Guanylate cyclase activating proteins (GCAPs) sense the fall and stimulate the ROS-GC catalytic activity to regenerate cGMP. As cGMP returns to the resting levels present in darkness, CNG channels re-open, Ca2+ enters and cGMP synthesis slows to its basal rate. In the presented pardigm, bicarbonate stimulates the membrane guanylate cyclase independently of Ca2+. But in the presence of GCAPs and low Ca2+, the impact of bicarbonate is greater than the sum of each factor in isolation. This synergism between bicarbonate and GCAPs at low Ca2+ has the physiological effect of boosting the maximal response amplitude, quickening photon response recovery and reducing sensitivity to flashes and to steady light.