In fluid-phase pinocytosis, small invaginations of the cell membrane form and entrap extracellular fluid and anything in solution in the fluid. Pinocytotic vesicles (about 80 nm in diameter) pinch off from the cell surface (Figure 4–25) and most eventually fuse with lysosomes (see the section on Lysosomes later in this chapter). In the lining cells of capillaries (endothelial cells), however, pinocytotic vesicles may move to the surface opposite their origin. There they fuse with the plasma membrane and release their contents onto the cell surface, thus accomplishing bulk transfer of material across the cell (Figure 11–4).
Receptors for many substances, such as low-density lipoproteins and protein hormones, are located at the cell surface. The receptors are either originally widely dispersed over the surface or aggregated in special regions called coated pits. Binding of the ligand (a molecule with high affinity for a receptor) to its receptor causes widely dispersed receptors to accumulate in coated pits (Figure 2–7). The coating on the cytoplasmic surface of the membrane is composed of several polypeptides, the major one being clathrin. These proteins form a lattice composed of pentagons and hexagons very similar in arrangement to the struts in a geodesic dome. The coated pit invaginates and pinches off from the cell membrane, forming a coated vesicle that carries the ligand and its receptor into the cell.
Schematic representation of the endocytic pathway and membrane trafficking. Ligands, such as hormones and growth factors, bind to specific surface receptors and are internalized in pinocytotic vesicles coated with clathrin and other proteins. After the liberation of the coating molecules, the pinocytotic vesicles fuse with the endosomal compartment, where the low pH causes the separation of the ligands from their receptors. Membrane with receptors is returned to the cell surface to be reused. The ligands typically are transferred to lysosomes. The cytoskeleton with motor proteins is responsible for all vesicle movements described.
The coated vesicles soon lose their clathrin coat and fuse with endosomes, a system of vesicles (Figure 2–7) and tubules located in the cytosol near the cell surface (early endosomes) or deeper in the cytoplasm (late endosomes). Together they constitute the endosomal compartment. Whether early and late endosomes are separate compartments or one is a precursor of the other is still an open question. The membrane of all endosomes contains ATP-driven H+ pumps that acidify their interior. The clathrin molecules separated from the coated vesicles are moved back to the cell membrane to participate in the formation of new coated pits.
Molecules penetrating the endosomes may take more than one pathway (Figure 2–7). Receptors that are separated from their ligand by the acidic pH of the endosomes may return to the cell membrane to be reused. For example, low-density lipoprotein receptors (Figure 2–8) are recycled several times. The ligands typically are transferred to late endosomes. However, some ligands are returned to the extracellular milieu to be used again. An example of this activity is the iron-transporting protein transferrin.
Internalization of low-density lipoproteins (LDL) is important to keep the concentration of LDL in body fluids low. LDL, which is rich in cholesterol, binds with high affinity to its receptors in the cell membranes. This binding activates the formation of pinocytotic vesicles from coated pits. The vesicles soon lose their coating, which is returned to the inner surface of the plasmalemma: the uncoated vesicles fuse with endosomes. In the next step, the LDL is transferred to lysosomes for digestion and separation of their components to be utilized by the cell.