How do small hydrophilic nonelectrolytes cross cell membranes? Which pathways are most important for small lipid insoluble molecules to cross cell membranes? These are questions that have been basic to membrane transport physiology for decades. More importantly, these are questions whose answers have changed significantly within the last 10 years. This review discusses the evidence that pathways other than the lipid bilayer itself exist for the transport across cell membranes of specific small hydrophilic nonelectrolytes. The description begins with briefly analyzing the relevance of well accepted basic mathematical models for transport for understanding the permeability of representative physiologically important molecules across actual cell membranes. Particular emphasis is placed on describing recently discovered proteins that facilitate the transport of some of the smallest physiologically important lipid-insoluble molecules, water, and urea. Evidence also exists for transport proteins that selectively enhance the transmembrane transport of other small lipid-insoluble molecules. Do nonselective pores for small molecules exist in cell membranes?

Key words: aquaporins; urea transporters; nonselective pores; membrane transport