Keeping track of neurotrophin receptors

Abstract

Mark Bothwell Department of Physiology and Biophysics University of Washington Seattle, Washington 98195 In the manner of many other growth factors, the prototypi- cal neurotrophic factor, nerve growth factor (NGF), has recently been found to be a member of a small gene family encoding structurally and functionally related proteins, collectively referred to as neurotrophins. Individual neuro- trophins exert similar functional effects, but on different neuronal populations. Each of the neurotrophins de- scribed to date-NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3)-interacts with cell- surface receptors that are heterogeneous with regard to binding affinity. For NGF and BDNF, analysis of equilib- rium binding data indicates the existence of two receptor populations with dissociation constants of about IO-” M (“high affinity”) and 10e9 M (“low affinity”) (Sutter et al., 1979; Rodriguez-TBbar and Barde, 1988). The low affinity receptor binds NGF, BDNF, and NT-3 with similar affinity, while high affinity receptors exist that bind either NGF or BDNF selectively (Rodriguez-TBbar et al., 1990; Squint0 et al., 1991). Functional response to aneurotrophin appar- ently is mediated specifically by the high affinity receptors. Rodriguez-TBbar et al. have proposed that there is a shared component of neurotrophin receptors, known as ~75, with the specificity of each receptor determined by a second component. A variety of studies have shown that low and high affinity NGF receptor forms are intercon- vertible. The interrelationshipsof thevarious neurotrophin recep- tors and of their high and low affinity forms have now been described. The emerging story has profound implications for neurobiology and quite probably for the biology of non- neural tissues also. The first neurotrophin receptor molecular clones iso- lated (Johnson et al., 1986; Radeke et al., 1987) encode a 75-80 kd intrinsic membrane protein (~75) that binds NGF, BDNF, and NT-3 with comparable low affinity (Kd of 10d9 M) when expressed in fibroblastic cells (Rodriguez- Tb Squintoet al., 1991). ~75 has a relatively small cytoplasmic domain containing none of the struc- tural motifs known to function in signal transduction in other receptors. Yet, transfection of ~75 cDNA clones into appropriate neuronal cell lines generates both high and low affinity NGF binding and renders these cells func- tionally responsive to NGF with regard to gene induction and enhanced neurite outgrowth (e.g., Hempstead et al., 1989). The response of such cell lines is weak in comparison with the response of primary neuronal cultures and the rat PC12 neuronal cell line, which expresses endogenous high affinity NGF receptors. The meager cellular response of transfected neuronal cell lines expressing ~7.5 may be