Caveolae as organizers of pharmacologically relevant signal transduction molecules

Abstract

Caveolae, a subset of membrane (lipid) rafts, are flask-like invaginations of the plasma membrane that contain caveolin proteins, which serve as organizing centers for cellular signal transduction. Caveolins (-1, -2, and -3) have cytoplasmic N and C termini, palmitolylation sites, and a scaffolding domain that facilitates interaction and organization of signaling molecules so as to help provide coordinated and efficient signal transduction. Such signaling components include upstream entities (e.g., G protein-coupled receptors (GPCRs), receptor tyrosine kinases, and steroid hormone receptors) and downstream components (e.g., heterotrimeric and low-molecular-weight G proteins, effector enzymes, and ion channels). Diseases associated with aberrant signaling may result in altered localization or expression of signaling proteins in caveolae. Caveolin-knockout mice have numerous abnormalities, some of which may reflect the impact of total body knockout throughout the life span. This review provides a general overview of caveolins and caveolae, signaling molecules that localize to caveolae, the role of caveolae/caveolin in cardiac and pulmonary pathophysiology, pharmacologic implications of caveolar localization of signaling molecules, and the possibility that caveolae might serve as a therapeutic target.

Figure 1

Microscopic and biochemical evaluation of caveolae. (a) Electron microscopic image of a caveola in pulmonary artery smooth muscle cells (8900x). (b) Sucrose density gradient separation of caveolae from disrupted cellular membranes. Resulting fractions were probed on the caveolin immunoblot (Cav IB) for the caveolar marker caveolin (right) and show enrichment in buoyant fractions (BF), which are thus representative of caveolae, but were not present in heavy fractions (HF), which localize other cellular membranes.

Figure 2

Caveolin scaffolding domain. Schematic depicting caveolae, resident structural proteins, caveolin (with its topology in the plasma membrane), and certain binding partners that interact with the caveolin scaffolding domain (CSD, green). The CSD is a peptide sequence (with the single letters reflecting its amino acids) that contains binding motifs [Φ representing aromatic amino acids, e.g., tyrosine (Tyr), tryptophan (Trp), or phenylalanine (Phe), and X representing other amino acids] that scaffold signaling molecules: adenylyl cyclase (AC), heterotrimeric Gα and Gβγ, Src, PI3 kinase (PI3K), endothelial nitric oxide synthase (eNOS, NOS 3), protein kinase A (PKA), protein kinase C (PKC), and mitogen activated protein kinase (MAPK, ERK).