A globin fragment, LVV-hemorphin-7, induces [³H]thymidine incorporation in a neuronal cell line via the AT₄ receptor

The AT₄ receptor was characterized initially as a specific binding site for angiotensin IV, a C-terminal fragment of the vasoactive peptide angiotensin II. Recently, we found that LVV-hemorphin-7, a fragment of β globin, is an abundant peptide in the brain and binds to the AT₄ receptor with high affinity and specificity. In the neuroblastoma/glioma hybrid cell line, NG108-15, LVV-hemorphin-7 and angiotensin IV competed for ¹²⁵I- angiotensin IV binding in a biphasic fashion with IC₅₀ values of 1.2 x 10 m and 1.1 x 10^-9 M for the high-affinity site, respectively, and 6.7 x 10^{- 8} and 1.5 x 10^-8 M for the low-affinity site, respectively. Both peptides were internalized rapidly by the cells. However, LVV-hemorphin-7, but not angiotensin IV, elicited a 1.8-fold increase in DNA synthesis in a dose- dependent manner. Furthermore, coincubation of the cells with an excess of angiotensin IV (10^-6 M) inhibited LVV-hemorphin-7-stimulated DNA synthesis. Therefore, whereas LVV-hemorphin-7 and angiotensin IV were capable of binding to the AT₄ receptor, only LVV-hemorphin-7 elicited [³H]thymidine incorporation in NG108-15 cells, n contrast, angiotensin IV behaved as an antagonist. The current finding suggests that LVV-hemorphin-7 is a functional peptide in the central nervous system and in view of its abundance in neural tissue, compared with angiotensin IV, may be of significant physiological importance.