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Thus, its use is closely monitored.■Vesicular Membrane TransportIn addition to movement through channels and transporters,certain substances can enter or be expelled from the cellthrough exocytosis, endocytosis, or transcytosis. These typesof movement through the cell membrane require ATP andinvolve packaging of the substances into lipid membranevesicles for transport (Fig. 2.5).■■cell (see Fig. 2.4). The active portion of this process is the original transport of Na+ against its gradient by the Na+/K+ pump;the subsequent events are secondary.

A typical example of 2° ATby symport is Na+-glucose and Na+-galactose transport acrossthe intestinal epithelium. An example of antiport is Na+/H+exchange that occurs in many cells, including renal and intestinal cells, in which Na+ enters the cells along its concentrationgradient through the antiporter while H+ leaves the cells.

TheNa+ pump also results in passive movement of ions throughchannels: Na+ (down its concentration gradient), Cl− (followingNa+ to preserve electroneutrality), and H2O (following theosmotic pressure gradient) (see Fig. 2.4C).ION CHANNELSMovement of ions occurs through channels in addition tomembrane carrier-mediated processes. Ion channels showhigh selectivity and allow specific ions to pass down theirLigand-gated channels are opened by the binding of aligand specific for that channel, such as acetylcholine(ACh). Binding of the ligand to its receptor causes thechannel to open, allowing ion movement. These are tetrameric or pentameric (four or five protein subunit)channels.Voltage-gated channels open in response to a change inmembrane voltage.

These channels are ion-specific andare composed of several subunits, with transmembranedomains forming a pathway for ion flux across themembrane.Gap junction channels (also called hemichannels) areformed between two adjacent cells and open to allowpassage of ions and small molecules between the cells.The hemichannels are generally hexameric (six subunits,or connexins).■Exocytosis involves fusion of vesicles to the cell membranefor extrusion of substances contained in the vesicles.Endocytosis is the process whereby a substance or particle outside the cell is engulfed by the cell membrane,forming a vesicle within the cell.

Phagocytosis is endocytosis of large particles; pinocytosis (“cell-drinking”) isendocytosis of fluid and small particles associated withthe engulfed fluid.Transcytosis occurs in capillary endothelial cells andintestinal epithelial cells to move material across the cellvia endocytosis and exocytosis.Vesicular packaging and transport is especially importantwhen the material needs to be isolated from the intracellularenvironment because of toxicity (antigens, waste, iron) orpotential for altering signaling pathways (e.g., Ca2+).AquaporinsIn addition to ion channels, there are specific water channelsor aquaporins that allow water to pass through the hydrophobic cell membrane, following the osmotic pressure gradient16Cell Physiology, Fluid Homeostasis, and Membrane Transport1⬚ Active3Na⫹1⬚ Active2° Active(symporter)2K⫹Na⫹3Na⫹XATPA2⬚ Active(antiporter)2K⫹Na⫹1⬚ Active3Na⫹YATPBPassive(channel)2K⫹Na⫹ATPCFigure 2.4 Secondary (2°) Active Transport While energy is not directly expended, secondaryactive transporters use a concentration gradient (usually for Na+) established by 1° active transporters tomove another substance in the same direction (symport, A), the opposite direction (antiport, B), or downthe concentration gradient of the ion (C).ExocytosisAEndocytosisBTranscytosisCFigure 2.5 Vesicular Transport through the Membrane A, Exocytosis; B, endocytosis;C, transcytosis.(Fig.

2.6). Many types of aquaporins (AQP) have been identified; the channels can be constitutively expressed in the membranes, or their insertion into the membrane can be regulated(for example, by antidiuretic hormone [ADH]; see Chapter18). As exemplified in the renal cortical collecting ducts,whereas AQP-3 is always present in the basolateral membranes of principal cells, regulation of water flux is throughinsertion of AQP-2 into the apical (lumenal) membranes.SIGNAL TRANSDUCTION MECHANISMSMuch of the basic regulation of cellular processes (e.g., secretion of substances, contraction, relaxation, production ofenzymes, cell growth, etc.) occurs by the binding of a regulatory substance to its receptor and the coupling of the receptorto effector proteins within the cell.Agonists, such as neurotransmitters, steroids, or peptide hormones, stimulate different transduction pathways.

The pathways frequently include activation of second messengersystems such as cAMP, cGMP, Ca2+, and IP3 (inositol trisphosphate). The second messengers can activate protein kinases,or in the case of Ca2+, calmodulin. The pathways can end inthe secretion of substances, release of ions, contraction orrelaxation of muscle, or regulation of transcription of specificgenes, as well as other processes.Membrane TransportExamples of some G protein–coupled ligands using thesepathways are given in Table 2.1, and some common signaltransduction pathways are outlined in Table 2.2.Protein KinasesMany transduction pathways work through the phosphorylation of proteins by protein kinases.

Protein kinase C (PK-C)OsmosisH 2O17can be activated by Ca2+, diacylglycerol (DAG), and certainmembrane phospholipids. Protein kinases, such as PK-A, canbe activated by the second messenger cAMP, and are designated “cAMP-dependent kinases.” There are also “cGMPdependent kinases.”Another critical pathway occurs via influx of Ca2+ throughligand-gated channels (Fig. 2.7), which results in activation ofCa2+-calmodulin–dependent kinases. These kinases are important in smooth muscle contraction, hormone secretion, andneurotransmitter release.H2OG Proteins (HeterotrimericGTP-Binding Proteins)Most membrane receptors are associated with G proteins(heterotrimeric GTP-binding proteins).

Ligand binding to themembrane-bound receptor-G-protein complex will causephosphorylation of GDP → GTP, allowing specific subunitsof the G protein to interact with different effector proteins(Fig. 2.8). The activated G proteins also have GTPase activity,which serves to inactivate the complex and end the process.Many hormones and peptides act through this general mechanism, and examples of several G protein–coupled receptorsare given in Table 2.1.Nuclear ReceptorsFigure 2.6 Water Channels Water flux follows the osmotic pressure gradient, and takes place through specific water channels, or aquaporins.

Water movement through aquaporins can be regulated byinsertion or removal of the proteins from the cell membrane.Table 2.1Several ligands, such as steroid hormones and thyroidhormone (T3), bind directly to their nuclear receptors, interact with the DNA, and increase or decrease transcription ofmRNA from target genes (Fig. 2.9). When this pathway isstimulated to increase protein synthesis, there is a delay inG ProteinsG ProteinActivated by Receptors forEffectorsSignaling PathwaysGsEpinephrine, norepinephrine,histamine, glucagon, ACTH,luteinizing hormone, folliclestimulating hormone, thyroidstimulating hormone, othersAdenylyl cyclaseCa2+ channels↑ Cyclic AMP↑ Ca2+ influxGolfOdorantsAdenylyl cyclase↑ AMP (olfaction)Gr1 (rods)PhotonsCyclic GMP phosphodiesterase↓ Cyclic GMP (vision)Gr2 (cones)PhotonsCyclic GMP phosphodiesterase↓ Cyclic GMP (color vision)Gi1, Gi2, Gi3Norepinephrine, prostaglandins, Adenylyl cyclaseopiates, angiotensin, manyPhospholipase CpeptidesPhospholipase A2K+ channels↓ Cyclic AMP↑ Inositol 1,4,5-trisphosphate, diacylglycerol, Ca2+Membrane polarizationGqAcetylcholine, epinephrine↑ Inositol 1,4,5-trisphosphate, diacylglycerol, Ca2+Phospholipase CβNote: There is more than one isoform of each class of a subunit.

More than 20 distinct α subunits have been identified.ACTH, Adrenocorticotropic hormone.(Reprinted with permission from Hansen J: Netter’s Atlas of Human Physiology, Philadelphia, Elsevier, 2002.)18Cell Physiology, Fluid Homeostasis, and Membrane TransportSignal Transduction PathwaysTable 2.2Adenylyl Cyclase(cAMP)PhospholipaseC (IP3 - Ca2+)Cytoplasmic/NuclearReceptorTyrosine KinaseGuanylate Cyclase (cGMP)ACTHGnRH*CortisolInsulinANPLHTRH*EstradiolIGFsNitric oxideFSHGHRH*ProgesteroneGHADH (V2 receptor)CRH*TestosteronePTHAngiotensin IIAldosteroneCalcitoninADH (V1 receptor)CalcitriolGlucagonOxytocinThyroid hormonesβ-Adrenergic agonistsα-Adrenergic agonistsSummary of some hormones, neurotransmitters, and drugs and the signal transduction pathways involved in their actions on cells.*Also increase intracellular cAMP.ACTH, Adrenocorticotropic hormone; ADH, antidiuretic hormone (vasopressin); ANP, atrial natriuretic peptide; CRH, corticotropin-releasing hormone;FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; IGF,insulin-like growth factor; LH, luteinizing hormone; PTH, parathyroid hormone; TRH, thyrotropin-releasing hormone.(Reprinted with permission from Hansen J: Netter’s Atlas of Human Physiology, Philadelphia, Elsevier, 2002.)CalmodulinCa2⫹Ligand-gatedCa2⫹ channelpresentation of the end protein because the process involvesgene transcription and translation.

This delayed action is incontrast to that of other hormones and ligands that releaseproteins from storage vesicles and thus can have a rapideffect.Simple vs. Complex PathwaysIncreased Ca2⫹Ca-CalmodulinDedicated CaM kinaseMultifunctional CaM kinaseEffectEffectFigure 2.7 Ca2+-Calmodulin Signal Transduction A goodexample of this mechanism is in stimulation of smooth muscle contraction, in which release of a neurotransmitter (such as tachykinin in gutsmooth muscle) will act on its receptors to open Ca2+ channels. Theincreased Ca2+ in the cytosol binds to calmodulin, which activates specific myosin kinases.

In this case, phosphorylation of myosin results inbinding to actin, causing crossbridge formation and contraction of themuscle.Transduction pathways can be relatively simple and fastacting, as is usually the case for the guanylate cyclase system(cGMP). This type of rapid effect is illustrated in the smoothmuscle relaxation response to nitric oxide (NO) released byvascular endothelial cells (Fig. 2.10). This is in contrast to thecomplex, slower transduction system observed in the multiplesteps involved in growth factor signal transduction, whereligand binding initiates a multistep process ending in nucleartranscription and protein synthesis (see Fig. 2.10).Membrane TransportAdenylylcyclaseReceptor␥␤␣␣␥␤␣␣G protein␣DAGPKC␣G proteincAMPATPR REffectIP3Ca2⫹R RC CCInactive PK-AAPhospholipase CReceptor19CEffectActive PK-AEndoplasmicreticulumBFigure 2.8 G Protein–Coupled Receptors Many ligands bind to receptors associated with membrane-bound G proteins to initiate transduction pathways.