BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 36. MEMBRANE TRANSPORT

36.18. Ions and Small Molecules Flow Directly from Cell to Cell through Gap Junctions

Large Water-filled channels that facilitate passive transport are a common feature of many prokaryotic and eukaryotic Introduction/36.html">Biological Membranes. For example, the outer membrane of Gram-negative Bacteria contains channels formed by porin, a transmembrane protein with a mass of 37 kDa (Sec. 32.14). Polar molecules with a mass of up to approximately 600 Da easily cross these 10 Å-wide channels to enter the periplasmic space. From there, these molecules are transported into the Cytosol via symport, group translocation, or other permeases. Similarly, the outer membranes of Cell/35.html">Mitochondria and METABOLISM/14.html">Chloroplasts contain large aqueous channels formed by molecules analogous to porin.

The most thoroughly characterized type of aqueous channel in eukaryotes is the gap junction (also known as an intercellular channel), which serves as a passageway between the interiors of adjacent Cells. Discovered by Jean-Paul Revel and Morris Karnovsky, Gap Junctions are clustered in specific Regions of the Plasma Membranes of adjoining cells. Cytology/cytology/93.html">ELECTRON MICROGRAPHS OF gap junction plaques (Fig. 36.28) reveal that each junction is composed of six subunits surrounding a pore 15-20 Å in diameter. A tangential section (Fig. 36.29) shows that these hexamers span the intercellular gap between contacting cells (hence the name gap junction). To determine the size exclusion limit of gap junctions, researchers microinjected a series of fluorescent probes into individual cells and observed the diffusion of fluorescence into neighboring cells. According to Werner Loewenstein, all polar molecules with a mass of up to 1 kDa readily pass through these intercellular channels. In other words, inorganic ions and most metabolites (sugars, Amino Acids, NUCLEOTIDES) can move freely from one cell to another via gap junctions. In contrast, Proteins, Nucleic Acids, and Polysaccharides are excluded from these channels due to their large size.

Class="center">Fig. 36.28. Electron micrograph of isolated intercellular gap junction plaques. Cylindrical connexons form a hexagonal lattice with a unit cell spacing of 85 Å. The diameter of the heavily stained central core is approximately 20 Å.

Fig. 36.29. Electron micrograph of a tangential section through gap junctions between adjacent cell membranes.

Gap junctions play a crucial role in Intercellular Communication. In several excitable Tissues, such as cardiac Muscle, cells are electrically coupled into a unified system by rapid ionic currents flowing through these junctions, thereby enabling a fast and synchronized response to stimulation. Gap junctions also supply nutrients to cells located far from Blood Vessels, such as those in bones or the lens of the eye. Furthermore, it is likely that these intercellular communication channels play a vital role in regulating developmental processes and cellular differentiation.

The permeability of gap junctions is regulated by Calcium Ions. An increase in intracellular Ca²⁺ concentration causes gap junctions to close to varying degrees. Intercellular channels are fully open at Ca²⁺ concentrations below 10^-7 M and completely closed at Ca²⁺ concentrations exceeding 5 • 10^-5 M. Elevating the Ca²⁺ concentration within this range leads to a narrowing of the intercellular channel lumen, with permeability decreasing first for larger molecules. The structural basis for these changes in channel diameter was elucidated by analyzing three-dimensional reconstructions of gap junction plaques in two states that differ in quaternary Structure. These structural studies demonstrated that a gap junction consists of two apposed cylindrical units called connexons. Each connexon is composed of six subunits, spans The Plasma Membrane, and is 75 Å long. A 20 Å segment of the connexon protrudes into the extracellular space to dock with the connexon of the neighboring cell. The long axis of each connexon subunit is tilted relative to the transverse axis of the membrane. Sliding of the subunits relative to one another reduces this tilt, leading to channel closure (Fig. 36.31). The most significant conformational changes occur at the midpoint of the channel, where the subunits of the two apposed connexons slide relative to each other by approximately 11 Å, corresponding to a 28° rotation. High-resolution analysis will help clarify precisely how Ca²⁺ induces this sliding and rotation.

Fig. 36.30. Schematic representation of a gap junction.

Fig. 36.31. Model of The regulation of gap junction closure by Ca²⁺ ions.