Caveolae, caveolin-1 and cavin-1: Emerging roles in pulmonary hypertension

Abstract

Caveolae are flask-shaped invaginations of cell membrane that play a significant structural and functional role. Caveolae harbor a variety of signaling molecules and serve to receive, concentrate and transmit extracellular signals across the membrane. Caveolins are the main structural proteins residing in the caveolae. Caveolins and another category of newly identified caveolae regulatory proteins, named cavins, are not only responsible for caveolae formation, but also interact with signaling complexes in the caveolae and regulate transmission of signals across the membrane. In the lung, two of the three caveolin isoforms, i.e., cav-1 and -2, are expressed ubiquitously. Cavin protein family is composed of four proteins, named cavin-1 (or PTRF for polymerase Ⅰ and transcript release factor), cavin-2 (or SDPR for serum deprivation protein response), cavin-3 (or SRBC for sdr-related gene product that binds to-c-kinase) and cavin-4 (or MURC for muscle restricted coiled-coiled protein or cavin-4). All the caveolin and cavin proteins are essential regulators for caveolae dynamics. Recently, emerging evidence suggest that caveolae and its associated proteins play crucial roles in development and progression of pulmonary hypertension. The focus of this review is to outline and discuss the contrast in alteration of cav-1 (cav-1),-2 and cavin-1 (PTRF) expression and downstream signaling mechanisms between human and experimental models of pulmonary hypertension.

Keywords: Caveolae; Caveolin-1; Cavin-1; Lipid rafts; Pulmonary hypertension.

Figure 1. Diagram summarizing the different functional domains of caveolin-1 protein

Cav-1 contains seven known functional domains. It contains an oligomerization domain (OD), a caveolin scaffolding domain (CSD), a transmembrane domain (TMD), a caveolin inhibitory domain (CID) (eNOS, Src kinase and PKA), a terminal domain (TD), an N-terminal membrane association domain (N-MAD), and a C-terminal membrane association domain (C-MAD). P-133, 143, 156: Palmitoylation sites.

Figure 2. Structural organizations of a caveola, caveolin-1 and cavin-1

Caveola are specialized lipid raft that are structurally maintained by caveolin-1 to form flask-shaped invaginations. In addition to these coat protein caveolin, caveolae contains an inner lining of adapter proteins called cavins, which regulate caveolin. PTRF: Polymerase Ⅰ and transcript release factor.

Figure 3. Schematic representation of alterations in caveolin-1 and the downstream pathways affected by caveolin-1 in human idiopathic pulmonary arterial hypertension and experimental models of pulmonary hypertension

Cav-1 expression is decreased in the lung. Downstream signaling pathways that are affected by cav-1 are diverse in different animal models of pulmonary hypertension (PH) and in humans. However, they eventually lead to vasoconstriction, vascular remodeling and development of PH. PAH: Pulmonary arterial hypertension; VEGFR: Vascular endothelial growth factor receptor; Cav-1: Caveolin-1.