We have previously shown the presence of calcium-sensing receptors (CaSR) in the human heart. In other tissues, CaSR were described to participate in the regulation of cell differentiation, hormone secretion etc. in response to local changes in extracellular Ca²⁺ (Ca²⁺e). We investigated the function of CaSR in the human atria. Methods: Function of CaSR was investigated by stimulation of atrial tissue with 4 mmol/l Ca²⁺e, in the presence and absence of specific CaSR-blocker Calhex231 and subsequent examination of its downstream signaling pathway. Transcriptional activity was investigated by Nuclear Transcription Factor (NTF) Protein/DNA array and electrophoretic mobility shift assay (EMSA). Results: Stimulation of atrial tissue with high Ca2+e (4 mmol/l) resulted in increased connexin40 expression (Cx40; factor of change from control: 1.26±0.15). After treatment with Calhex231 (C231), Cx40 expression was significantly decreased (factor of change from control: 0.52±0.18; p<=0.03 vs. 4 mmol/l Ca²⁺e). Investigation of the downstream targets of CaSR revealed, that increase in phosphorylation of extracellularly regulated kinase 1 and 2 (ERK1/2) due to stimulation with 4 mmol/l Ca²⁺e as well as the decrease after concomitant C231 treatment were both non-significant (p>=0.05). However, p38 MAPK phosphorylation was significantly reduced by treatment with Calhex231 (factor of change from control: C231 0.59±0.17 vs. 4 mmol/l Ca²⁺e 1.33±0.26; p<=0.03). Moreover, after stimulation with 4 mmol/L Ca²⁺e the NTF Protein/DNA array as well as EMSA, both detected increased activities of retinoic acid receptors and thyroid hormone receptors as compared with 2 mmol/l Ca²⁺e. C231 could also prevent this increase in transcription factors activities. Conclusion: We demonstrate the functional response of CaSR in the human atria and show relation of CaSR to Cx40 expression and hypertrophy pathway.