Unraveling the Cave: A Seventy-Year Journey into the Caveolar Network, Cellular Signaling, and Human Disease

Abstract

In the mid-1950s, a groundbreaking discovery revealed the fascinating presence of caveolae, referred to as flask-shaped invaginations of the plasma membrane, sparking renewed excitement in the field of cell biology. Caveolae are small, flask-shaped invaginations in the cell membrane that play crucial roles in diverse cellular processes, including endocytosis, lipid homeostasis, and signal transduction. The structural stability and functionality of these specialized membrane microdomains are attributed to the coordinated activity of scaffolding proteins, including caveolins and cavins. While caveolae and caveolins have been long appreciated for their integral roles in cellular physiology, the accumulating scientific evidence throughout the years reaffirms their association with a broad spectrum of human disorders. This review article aims to offer a thorough account of the historical advancements in caveolae research, spanning from their initial discovery to the recognition of caveolin family proteins and their intricate contributions to cellular functions. Furthermore, it will examine the consequences of a dysfunctional caveolar network in the development of human diseases.

Keywords: ECs; calcium signaling; caveolae; caveolin-1; cell senescence; eNOS; endocytosis; lipid rafts; signal transduction.

Figure 1

Timeline of caveolae research. The diagram depicts significant observations in caveolae biology from their discovery to the present, emphasizing their suggested participation in diverse cellular processes. It is important to highlight that the “caveolae signaling hypothesis” and the participation of caveolin domains in protein–protein interactions should be re-evaluated in light of recent cryoEM studies on caveolin, as discussed in this review article.

Figure 2

Schematic illustration of caveolin-1. CRAC sequence “VTKYWFYR” spanning residues 94–101; CSD, caveolin scaffolding domain; CSM, caveolin signature motif “FEDVIAEP”; OD, oligomerization domain; TDM, transmembrane domain. Two phosphorylation sites at tyrosine 14 (Y14) and serine 80 (S80) are indicated. Cavin proteins directly interact with caveolins, forming a stable complex that is critical for the formation of caveolae and their localization in the plasma membrane.

Figure 3

Schematic representation of the caveolin family of proteins. CRAC, cholesterol recognition/interaction amino acid consensus; OD, oligomerization domain; TDM, transmembrane domain; CSD, caveolin scaffolding domain.