Regulation and function of the CGRP receptor complex in human granulopoiesis

Anatomic studies and animal experiments suggest that neuropeptides such as calcitonin gene-related peptide (CGRP) may be involved in hematopoiesis. Here, we examined the regulation and function of the CGRP receptor in human granulopoiesis.

Expression of CGRP receptor components on CD34(+) cells, peripheral blood granulocytes, and in vitro differentiated CD34(+) cells was analyzed at the mRNA level and by measuring the signaling capacity of the receptor. The function of CGRP in human hematopoiesis was investigated by clonal colony formation assays.

mRNA transcripts for the cell surface CGRP receptor subunits receptor activity-modifying protein-1 (RAMP-1) and calcitonin receptor-like receptor (CRLR) as well as for the intracellular adapter protein CGRP-receptor component protein (CGRP-RCP) were found in CD34(+) cells from 4/4 donors tested. CGRP-RCP mRNA was expressed in peripheral blood granulocytes of 8/15 donors, whereas RAMP-1 and CRLR were not detectable. CD34(+) cells, but not granulocytes, exhibited a marked elevation of cellular cAMP after CGRP stimulation, thereby confirming the mRNA expression data. Both RAMP-1 and CRLR mRNA expression and CGRP receptor signaling capacity were lost during in vitro granulocytic differentiation of CD34(+) cells. Consistent with a role of CGRP in hematopoiesis, we show that CGRP significantly enhances the formation of granulomonocytic, but not erythroid or mixed, colonies by purified human CD34(+) cells.

The CGRP receptor is expressed on CD34(+) hematopoietic progenitor cells and is downregulated during granulocytic differentiation. CGRP directly acts on CD34(+) cells to promote formation of granulomonocytic colonies. Thus, CGRP may have a function in directing hematopoiesis.