G-protein coupled receptors (GPCRs) are commonly present at the plasma membrane and their signaling modulates excitation-contraction coupling and excitation-secretion coupling of excitable and non-excitable cells of the cardiovascular system. Their effect on excitation-gene expression coupling was attributed, in part, to the nuclear translocation of their signaling and/or to the entry into the nuclear membrane of the internalized GPCRs. However, the recently established paradigm showed that, in addition to plasma membrane G-proteins, GPCRs exist as native nuclear membranes receptors and they modulate nuclear ionic homeostasis and function. These nuclear membrane GPCRs could function independently of plasma membrane GPCRs. Growing evidence also shows that these nuclear membrane GPCRs contribute to protein synthesis and also undergo changes in pathological conditions. The presence of a GPCR at both the plasma and nuclear membranes and/or only at the nuclear membranes represents a new challenge to better understand their contribution to cell physiology and pathology and, consequently, to the development of new therapeutic drugs targeting this category of receptors.