Four distinct mammalian arrestin proteins are known. Arrestin 1 (also known as S-arrestin) and arrestin 4 (or X-arrestin) are localized to retinal rods and cones, respectively. Arrestin 2 (also known as beta-arrestin 1) and arrestin 3 (or beta-arrestin 2) are ubiquitously expressed and bind to most GPCRs. Members of arrestin/b-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. beta-arrestin 1 is a cytosolic protein and acts as a cofactor in the beta-adrenergic receptor kinase (BARK) mediated desensitization of beta-adrenergic receptors. Besides the central nervous system, it is expressed at high levels in peripheral blood leukocytes, and thus the BARK/b-arrestin system is believed to play a major role in regulating receptor-mediated immune functions. beta-arrestin 2 is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. beta-arrestin proteins function as adapters and scaffold proteins and play important roles in other processes, such as recruiting c-Src family proteins to GPCRs in ERK activation pathways. beta-arrestins are also involved in some receptor tyrosine kinase signaling pathways. Additional evidence suggests that beta-arrestin proteins translocate to the nucleus and help regulate transcription by binding transcriptional cofactors. Alternatively spliced transcripts encoding different isoforms of b-arrestin 1/2 have been described.