Several aminergic GPCRs, e.g., the human histamine H3-receptor (hH3R) are sensitive to sodium ions. Based on these experimental results, including site directed mutagenesis studies, a sodium binding pocket near to the highly conserved Asp2.50 was suggested. Recently, in the crystallized adenosine A2A receptor (4EIY), a sodium ion was found in a pocket, coordinated by Asp52, Ser91, and three water molecules. Despite high homology in amino acid sequence between hH3R and hH4R, pharmacological studies revealed that the hH4R is--in contrast to hH3R--not sensitive to sodium ions. In order to obtain a deeper insight onto the differences in sodium sensitivity between hH3R and hH4R, we performed molecular modelling studies, including molecular dynamic simulations and calculation of Gibbs energy of solvation. The results of the modeling studies suggested that the amino acid at position 7.42 influences sodium binding to aminergic GPCRs in different ways. A comparison of the amino acids forming the sodium binding channel between the ligand binding pocket and the sodium binding pocket of all human aminergic GPCRs showed an 80% occurrence of glycine--in contrast to hH3R and hH4R. The Gln7.42 at hH4R disrupts a water chain, connecting the Asp3.32 of the orthosteric binding site and the Asp2.50 of the allosteric binding site. Besides, the oxygen of the glutamine side chain stabilizes the interaction of the sodium ion with the Asp3.32. Thus, the binding of the sodium into the allosteric binding site might be hindered kinetically.