G protein-coupled receptor (GPCR) undergoes lost of responsiveness upon repeated stimulus. This phenomenon is known as homologous desensitization and is mediated by a class of S/T kinases named G protein-coupled receptor kinases (GRK). GRK family is composed of six cloned members, named GRK1 to 6. GRK functions are modulated by different calcium sensor proteins (CSP). In the presence of calcium, rhodopsin kinase (GRK1) is inhibited by the photoreceptor-specific CSP (Recoverin) through direct binding. Several other recoverin homologues (including NCS 1, VILIP 1 and hippocalcin) are also able to inhibit GRK1. The ubiquitous calcium-binding protein calmodulin (CaM) inhibit GRK5 phosphorylating activity with a high affinity through a direct interaction, however this binding does not influence the catalytic activity of the kinase, but rather reduced GRK5 binding to the membrane. Different CSP work as functional analogues to regulate different GRK subtypes in a Ca²⁺ dependent manner. CSP are selective regulators of GRK subtypes: while GRK1, but not GRK2 and GRK5, is regulated by recoverin and other NCS, GRK4, 5 and 6, that belong to the GRK4 subfamily, are potently inhibited by CaM, which had little or no effect on members of other GRK subfamilies.