Endocytosis and downregulation of G protein-coupled receptors

Parkinsonism & Related Disorders
Mark von Zastrow

Abstract

The number of G protein-coupled receptors (GPCRs) displayed at the cell surface is a critical determinant of physiological responsiveness to native ligands and drugs. Downregulation of the number of adrenergic and dopaminergic receptors present on specific neurons can be induced by receptor agonists or by drugs that increase extracellular concentrations of catecholamines such as dopamine. Thus agonist-induced downregulation of GPCRs is of potentially great importance to the treatment of Parkinson's Disease. However, little is known about biochemical mechanisms that mediate GPCR downregulation. Recent studies of cloned GPCRs have provided exciting insights into specific mechanisms that control endocytosis of receptors from the plasma membrane and regulate proteolytic degradation of receptors. In this review we briefly survey representative studies establishing that multiple mechanisms of GPCR membrane trafficking can function in downregulation function both in neural and non-neural cell types. Then we focus on our present view of mechanisms mediating regulated proteolysis of GPCRs, highlighting recent progress in understanding membrane trafficking of GPCRs from the cell surface to lysosomes. Finally we discuss emerging evidence ...Continue Reading

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