Up to now, transgenic mice models created to study the physiological impact of alterations in the human beta-adrenoceptor system have only focused on cardiac tissues and carried hybrid transgenes with strong cardiac promoters. We have developed a transgenic mouse strain (F28) carrying the human beta 2-adrenoceptor gene with its natural promoter region with the aim of producing a model that more closely reproduces the natural human beta 2-adrenoceptor tissue expression pattern. By means of northern blot analyses, using the appropriate probes, we have obtained evidence that (a) the human beta 2-adrenoceptor's structural gene is transcribed in several tissues of F28 mice; (b) the tissue distribution pattern of human beta 2-adrenoceptor mRNA in F28 mice completely differs from that of mouse beta 2-adrenoceptor mRNA; and (c) the tissue distribution pattern of mouse beta 2-adrenoceptor mRNA in F28 mice is very similar to that observed in their non-transgenic littermates. Like humans, F28 mice express human beta 2-adrenoceptor mRNA in liver, lung, brain, heart, and muscle. However, unlike humans, F28 mice do not accumulate human beta 2-adrenoceptor mRNA in kidney and spleen. By using [125I]iodocyanopindolol to label all beta-adrenoceptors and ICI 118,551 to discriminate between the binding to beta 2- and beta 1-adrenoceptors we have demonstrated that the beta 2-adrenoceptor binding activity increases over control values in F28 mouse tissues that accumulate transgenic mRNA. Accordingly, the number of beta 2-adrenoceptors increased slightly over the control values in muscle, heart, brain, and lung of F28 mice, while in liver these receptors were strongly overexpressed. We further showed that transgene beta 2-adrenoceptors couple to GTP-binding proteins, mediate beta-adrenoceptor agonist-stimulated adenylyl cyclase activation, and cause a strong enhancement of this response in liver membranes of F28 versus control mice. Finally, F28 mice show a phenotype of depressed ponderal development and perturbed hindquarter movements. This unique model should be useful to further investigate beta 2-adrenoceptor causal relationships with human pathologies.