Ca2+-binding proteins in the retina: from discovery to etiology of human disease

Examination of the role of Ca2+-binding proteins (CaBPs) in mammalian retin al neurons has yielded new insights into the function of these proteins in normal and pathological states. In the last 8 years, studies on guanylate c yclase (GC) regulation by three GC-activating proteins (GCAP1-3) led to sev eral breakthroughs, among them the recent biochemical analysis of GCAP1(Y99 ) mutants associated with autosomal dominant cone dystrophy. Perturbation o f Ca2+ homeostasis controlled by mutant GCAP1 in photoreceptor cells may re sult ultimately in degeneration of these cells. Here, detailed analysis of biochemical properties of GCAP1(P50L), which causes a milder form of autoso mal dominant cone dystrophy than constitutive active Y99C mutation, showed that the P50L mutation resulted in a decrease of Ca2+-binding, without chan ges in the GC activity profile of the mutant GCAP1. In contrast to this bio chemically well-defined regulatory mechanism that involves GCAPs, understan ding of other processes in the retina that are regulated by Ca2+ is at a ru dimentary stage. Recently, we have identified five homologous genes encodin g CaBPs that are expressed in the mammalian retina. Several members of this subfamily are also present in other tissues. In contrast to GCAPs, the fun ction of this subfamily of calmodulin (CaM)-like CaBPs is poorly understood . CaBPs are closely related to CaM and in biochemical assays CaBPs substitu te for CaM in stimulation of CaM-dependent kinase II, and calcineurin, a pr otein phosphatase. These results suggest that CaM-like CaBPs have evolved i nto diverse subfamilies that control fundamental processes in cells where t hey are expressed. (C) 2000 Elsevier Science B.V. All rights reserved.