Serotonin 5-HT 4 receptor isoforms are G protein-coupled receptors (GPCRs) with distinct pharmacological properties and may represent a valuable target for the treatment of many human disorders. Here, we have explored the process of dimerization of human 5-HT 4 receptor (h5-HT 4 R) by means of co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Constitutive h5-HT 4(d) R dimer was observed in living cells and membrane preparation of CHO and HEK293 cells. 5-HT 4 R ligands did not influence the constitutive energy transfer of the h5-HT 4(d) R splice variant in intact cells and isolated plasma membranes. In addition, we found that h5-HT 4(d) R and h5-HT 4(g) R which structurally differ in the length of their C-terminal tails were able to form constitutive heterodimers independently of their activation state. Finally, we found that coexpression of h5-HT 4 R and β 2 -adrenergic receptor (β 2 AR) led to their heterodimerization. Given the large number of h5-HT 4 R isoforms which are coexpressed in a same tissue, our results points out the complexity by which this 5-HTR sub-type mediates its biological effects.