Membrane Glucocorticoid Receptors and Glucocorticoid Signal Transduction

Abstract

Membrane forms of some steroid hormone receptors (mSRs) were first reported almost three decades ago [(1, 2, 3),and references therein, but only recently have their identities and functions received intense focus by a growing number of laboratories. As a result, relatively little is known about the mSRs’ biochemical characteristics, molecular structure, protein targeting pathways, and the specific nature of their residence in the plasma membrane. Work conducted in our laboratory over the last 15 years, in several murine and human lymphoid cell lines, described a membrane form of the “nuclear” glucocorticoid receptor (mGR) whose level of expression is more strongly correlated with glucocorticoid (GC)-evoked lymphocytosis than is the intracellular GR (iGR) (4, 5, 6, 7, 8, 9, 10, 11, 12). This suggests that the GC-evoked signaling associated with apoptosis in lymphoid cells is initiated by a necessary mGR, and portends a great clinical importance for its measurement and manipulation in the treatment of lymphoproliferative diseases. Our studies began by demonstrating the existence of mGRs and capturing a population of cells enriched in the mGR, to perform correlative functional studies. We then more closely defined the characteristics of the mGR protein and established connections between mGR and the initiation of specific signaling cascades that terminate in apoptosis.