In many peripheral tissues, calcitonin gene-related peptide (CGRP) is released from peptidergic sensory nerve fibres and acts like a growth factor during tissue development and regeneration. However, the ability of CGRP to influence gingival tissue has not been studied. To address this question, we have now examined the effects of CGRP on the proliferation of human gingival fibroblasts (Gin-1) in vitro. Gin-1 cells have approximately 3100 specific CGRP-binding sites with a Kd of 38.6 pM on their surface. Treatment with CGRP (0.1-100 nM) significantly stimulated cell proliferation in a dose-dependent manner, with maximal effects at 1-10 nM CGRP after 2 d. As one early cellular response to CGRP, p44-MAPK protein (also known as the extracellular signal response kinase [ERK]) was tyrosine- and threonine-phosphorylated within 2 min, and this phosphorylation was sustained for at least 1 h. The dose-response curve of MAPK activation was very similar to that observed for CGRP's stimulation of cell proliferation. In addition, CGRP's activation of MAPK stimulated its ability to phosphorylate the Elk-1 transcription factor. When cells were pretreated with PD98059, a selective inhibitor of MAPK kinase (also known as MEK), CGRP not only failed to induce phosphorylation of MAPK but also failed to stimulate Gin-1 cell proliferation. Our present data indicate that CGRP rapidly activates the MAPK signalling pathway, an effect which consequently stimulates the proliferation of gingival fibroblasts. Our data demonstrate specific cellular responses to CGRP by gingival fibroblasts and support the possibility that CGRP acts as a targeted local factor in the regulation of development, generation and/or regeneration of gingival tissues.