| Transport by channels and pores
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| An 18-month-old child presented with polyuria, failure to thrive and an episode of severe dehydration. Urine dipstick testing demonstrated glucosuria and proteinuria, with other biochemical analyses showing generalized aminoaciduria and phosphaturia. |
| Comment. This is a classical presentation of infantile cystinosis, resulting from accumulation of cystine in lysosomes because of a defect in the lysosomal transport protein, cystinosine. Cystine is poorly soluble, and crystalline precipitates form in cells throughout the body. In vitro experiments with cystine loading have shown that renal proximal tubular cells become ATP-depleted, resulting in impairment of ATP-dependent ion pumps with consequent electrolyte and metabolite losses. Treatment with cysteamine increases the transport of cystine from lysosomes, delaying the decline in renal function. If untreated, renal failure occurs by 6-12 years of age. Unfortunately, there is further accumulation of cystine in the central nervous system, despite therapy, with long-term neurological damage. |
| Channels are often pictured as tunnels across the membrane, in which binding sites for substrates (ions) are accessible from either side of the membrane at the same time (Fig. 7.3B). Conformational changes are not required for the translocation of
substrates entering from one side of the membrane to exit on the other side. However, voltage changes and ligand binding induce conformational changes in channel structure that have the effect of opening or closing the channels - processes known as voltage or ligand 'gating'. Movement of molecules through channels is fast (107-108/s) in comparison with the rates achieved by transporters (Table 7.3).
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| The terms 'channel' and 'pore' are sometimes used interchangeably. However, 'pore' is used most frequently to describe more open, somewhat nonselective structures that discriminate between substrates, e.g. peptides or proteins on the basis of size. The term 'channel' is usually applied to describe more specific ion channels.
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Table 7-4.
Classification of glucose transporters. |
| Body_ID: None |
Classification of glucose transporters |
| Body_ID: T007004.50 |
| Transporter | Kt for d-glucose transport (mM) | Substrate | Major sites of expression |
| Body_ID: T007004.100 |
| Facilitated diffusion (uniporter) (passive transport) |
| Body_ID: T007004.150 |
| GLUT-1 | 1-2 | glucose, galactose, mannose | ubiquitous (erythrocyte, blood-tissue barriers) |
| Body_ID: T007004.200 |
| GLUT-2 | 15-20 | glucose, fructose | liver, intestine, kidney, pancreatic β-cells, brain |
| Body_ID: T007004.250 |
| GLUT-3 | 1.8* | glucose | ubiquitous |
| Body_ID: T007004.300 |
| GLUT-4 | 5 | glucose | skeletal and cardiac muscles, adipose tissues |
| Body_ID: T007004.350 |
| GLUT-5 | 6-11** | fructose | intestine |
| Body_ID: T007004.400 |
| Na+-coupled symporter (active transport) |
| Body_ID: T007004.450 |
| SGLT-1 | 0.35 | glucose (2Na+/1glucose), galactose | intestine, kidney |
| Body_ID: T007004.500 |
| SGLT-2 | 1.6 | glucose (1Na+/1glucose) | kidney |
| Body_ID: T007004.550 |
Km values are determined from the uptake of 2-deoxy-d-glucose (*)
a non-metabolizable analog of glucose, and fructose (**).
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| page 84 |  | | page 85 |
| A three-year old had been on holiday to Spain and developed pellagra-like skin changes on his face, neck, forearms and dorsal aspects of his hands and legs. His skin became scaly, rough and hyperpigmented. The child was brought to the GP complaining of headaches and weakness. Urinalysis demonstrated gross hyperaminoaciduria of neutral monoamino-monocarboxylic acids (i.e. alanine, serine, threonine, asparagine, glutamine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine and citrulline). |
| Comment. These neutral amino acids share a common transporter which is expressed only on the luminal border of epithelial cells in the renal tubules and intestinal epithelium. The pellagra-like dermatitis (see Chapter 10) and neurological involvement resemble nutritional niacin deficiency. The reduced tryptophan intake results in reduced nicotinamide production. The disease is easily treated with oral nicotinamide and sun-blocking agents to exposed areas. |
| Three examples of pores important for cellular physiology
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| The gap junction between endothelial, muscle, and neuronal cells is a cluster of small pores, in which two cylinders of six connexin subunits in plasma membranes join each other to form a pore about 1.2-2.0 nm (12-20 Å) in diameter. Molecules smaller than about 1 kDa can pass between cells through gap junctions. Such cell-cell communication is important for physiologic coupling, for example in the concerted contraction of uterine muscle during labor and delivery. These pores are usually maintained in an open state, but will close when cell membranes are damaged or when the metabolic rate is depressed. Mutations of the genes encoding connexin 26 and connexin 32 cause deafness and Charcot-Marie-Tooth disease, respectively.
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| Nuclear pores have a functional radius of about 9.0 nm (90 Å) through which proteins and nucleic acids enter and leave the nucleus.
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| A third class of pores is important for protein sorting. Mitochondrial proteins encoded by nuclear genes are transported to this organelle through pores in the outer mitochondrial membrane. Nascent polypeptide chains of secretory proteins and plasma membrane proteins also pass through pores in the endoplasmic reticulum membrane.
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