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Extranuclear Steroid Receptors: Nature and Actions

Division of Endocrinology and the Departments of Medicine and Pharmacology (S.R.H.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Division of Endocrinology (E.R.L.), Veterans Affairs Medical Center, Long Beach, Long Beach, California 90822; and Departments of Medicine, Biochemistry, and Pharmacology (E.R.L.), University of California, Irvine, Irvine, California 92697

Correspondence: Address all correspondence and requests for reprints to: Stephen R. Hammes, M.D., Ph.D., University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: stephen.hammes{at}utsouthwestern.edu; or Ellis R. Levin, M.D., Medical Service (111-I), Long Beach VA Medical Center/University of California-Irvine, 5901 East 7th Street, Long Beach, California 90822. E-mail: ellis.levin{at}va.gov

Rapid effects of steroid hormones result from the actions of specific receptors localized most often to the plasma membrane. Fast-acting membrane-initiated steroid signaling (MISS) ¹leads to the modification of existing proteins and cell behaviors. Rapid steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this and other ways, the integration of all steroid actions in the cell coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of intense interest, and significant data suggest that extranuclear and nuclear steroid receptor pools are the same proteins. Insights regarding the structural determinants for membrane localization and function, as well as the nature of interactions with G proteins and other signaling molecules in confined areas of the membrane, have led to a fuller understanding of how steroid receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo functions of steroid hormones has been established. Examples include steroid effects on reproductive organ development and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In this review, we highlight the significant progress that has been made in these areas.

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