The definition of a channel (or a pore) is that of a protein structure that facilitates the translocation of molecules or ions across the membrane through the creation of a central aqueous channel in the protein. This central channel facilitates diffusion in both directions dependent upon the direction of the concentration gradient. Channel proteins do not bind or sequester the molecule or ion that is moving through the channel. Specificity of channels for ions or molecules is a function of the size and charge of the substance. The flow of molecules through a channel can be regulated by various mechanisms that result in opening or closing of the passageway.
Membrane channels are of three distinct types. The α-type channels are homo- or hetero-oligomeric structures that in the latter case consist of several dissimilar proteins. This class of channel protein has between 2 and 22 transmembrane α-helical domains which explains the derivation of their class. Molecules move through α-type channels down their concentration gradients and thus require no input of metabolic energy. Some channels of this class are highly specific with respect to the molecule translocated across the membrane while others are not. In addition, there may be differences from tissue to tissue in the channel used to transport the same molecule. As an example, there are over 15 different K+-specific voltage-regulated channels in humans.
The transport of molecules through α-type channels occurs by several different mechanisms. These mechanisms include changes in membrane potential (termed voltage-regulated or voltage-gated), phosphorylation of the channel protein, intracellular Ca2+, G-proteins, and organic modulators.
Aquaporins (AQP) are a family of α-type channels responsible for the transport of water across membranes. At least 11 aquaporin proteins have been identified in mammals with 10 known in humans (termed AQP0 through AQP9). A related family of proteins is called the aquaglyceroporins which are involved in water transport as well as the transport of other small molecules. AQP9 is the human aquaglyceroporin. The aquaporins assemble in the membrane as homotetramers with each monomer consisting of six transmembrane α-helical domains forming the distinct water pore. Probably the most significant location of aquaporin expression is in the kidney. The proximal tubule expresses AQP1, AQP7, and AQP8, while the collecting ducts express AQP2, AQP3, AQP4, AQP6, and AQP8. Loss of function of the renal aquaporins is associated with several disease states. Reduced expression of AQP2 is associated with nephrogenic diabetes insipidus (NDI), acquired hypokalemia, and hypercalcemia.
Diagrammatic representations of the structure of an aquaporin. Top pane shows the linear array of the protein indicating the two regions of helical domains that interact to form the three dimensional orientation of the protein. The pore that forms in the aquaporins is composed of two halves referred to as hemipores. Amino acids of the pore that are critical for water transport are the asparagine (N), proline (P) and alanine (A) residues indicated in each hemipore. Bottom panel shows how the two hemipores interact to form the functional aquaporin.
The β-barrel channels (also called porins) are so named because they have a transmembrane domain that consists of β-strands forming a β-barrel structure. Porins are found in the outer membranes of mitochondria. The mitochondrial porins are voltage-gated anion channels that are involved in mitochondrial homeostasis and apoptosis.
The pore-forming toxins represent the third class of membrane channels. Although this is a large class of proteins first identified in bacteria, there are a few proteins of this class expressed in mammalian cells. The defensins are a family of small cysteine-rich antibiotic proteins that are pore-forming channels found in epithelial and hematopoietic cells. The defensins are involved in host defense against microbes (hence the derivation of their name) and may be involved in endocrine regulation during infection.