Membrane Transport

Key Concepts

• Free energy of transporting material across membrane depends on concentration gradient across membrane:
  
  • Solutes move spontaneously (DG_t < 0) from compartment of higher concentration to compartment of lower concentration.
    Equilibrium: DG = 0 when C₁ = C₂
    

• Charged solutes: presence of a membrane potential as well as the chemical concentration gradient influences the distribution of ions:
  
  
• Uniport (system in which one solute transported)
• Cotransport (system in which transport of one solute is coupled to transport of another)
  • Symport (different solutes transported in same direction)
  • Antiport (different solutes transported in opposite directions)
    
    
• Passive transport is spontaneous passage of solute "down" its concentration and/or electrical potential gradient -- no input of free energy required.
  • simple diffusion (no assistance)
  • facilitated diffusion (rate enhanced by carrier or channel, generally an integral membrane protein (transporter or permease)
    • rapid diffusion "down" a concentration gradient
    • saturable (reaches a maximum velocity that depends on transporter concentration
    • specific (depends on interaction of solute with transporter)
      
      
  • Gated ion channels (ligand-gated or voltage-gated)
    
    
• Active transport
  • Primary active transport (transport of solute against its concentration gradient, coupled directly to an exergonic chemical reaction, e.g., ATP hydrolysis)
  • Secondary active transport (energy from ATP hydrolysis is used to generate a gradient of another solute, and the transport of that solute "down" its concentration gradient is used to drive transport of a different solute against its concentration gradient)

• Transport processes involving membrane proteins usually involve protein conformational changes.
  

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Cellular Transport

• Free energy of transporting material across membrane depends on concentration gradient across membrane:
  
  • Solutes move spontaneously (DG_t < 0) from compartment of higher concentration to compartment of lower concentration
• DG = 0 when C₁ = C₂ (equilibrium)
• Diffusion "down" the concentration gradient (from region of greater concentration to region of lower concentration, toward equilibrium of equal concentrations) is a manifestation of the 2nd law of thermodynamics -- molecules tend spontaneously to assume the distribution of greatest randomness, i.e., entropy increases until system is maximally randomized.
• 3 ways to circumvent such concentration equalization:
  • Transported substance may be bound by a macromolecule inside the cell (or in the destination compartment).
    • lowers free concentration of substance within the cell/compartment, e.g., O₂ binding by hemoglobin.
  • It's the free concentration that is used in the above equation. 
  • Presence of a membrane potential influences the distribution of ions (charged solutes).
    • free energy change involved in transport of an ion: of charge Z,
      
      where Z = charge on the ion, F = the Faraday constant (96.5 kJ/(V•mol) and DY = the membrane potential (the charge gradient across the membrane, in volts, or millivolts, etc.)
    • If DY is negative, going from outside to inside, then the transport of cations into the cell is favored over anions. The opposite would be true if DY were positive.
  • Coupling of "uphill" (unfavorable) transport [RTln(C₂/C₁) > 0] to some thermodynamically favorable process (DG' < 0) such that overall DG_t < 0:
    
    
  • active transport: general term for processes in which cell expends energy to drive transport -- uptake of a needed compound or secretion of a waste product.
    • Primary active transport: energy from an exergonic chemical reaction, e.g., ATP hydrolysis, is used to drive the process directly.
    • Secondary active transport: energy from ATP hydrolysis is used to generate a gradient of another solute (e.g., protons or Na⁺), and cotransport of that other solute "down" its concentration gradient is used to drive the unfavorable process.
      • Gradient of 2nd solute is another way to "store" potential energy that can be tapped to drive an unfavorable process.
    • Such transport systems (proteins that couple 2 processes) are often called "pumps".
      
      
  • passive transport: general term for processes in which solute moves "down" its concentration gradient (C₂ < C₁), i.e. in the thermodynamically favored, "spontaneous", direction
    • simple diffusion: molecule freely passes through membrane in the direction dictated by concentration gradient; no "carrier" required.
      • depends on concentration gradient across membrane but does not use a carrier
      • examples of solutes that diffuse across membranes: O₂, N₂, methane (CH₄), H₂O (slow)
      • rate linearly dependent on solute concentration
    • facilitated diffusion: molecule moves in direction dictated by concentration gradient, but rate of transport is increased by a carrier molecule or specific protein in membrane.
      • mediated by proteins in membrane (transporters, or permeases)
        Proteins either
        • create pores (channels) through which the material can move or
        • serve as carriers to move material from one side of membrane to the other
      • Enhanced ("facilitated") rate
        • depends on concentration of carrier or pore as well as on solute concentration
        • shows solute specificity if protein binds solute for transport.
        • shows saturation behavior -- maximum transport rate (at which rate becomes independent of solute concentration) is proportional to concentration of carrier binding sites or pores.

Passive transport: cells take up materials by either Simple diffusion or Facilitated diffusion/transport

• ionophores = compounds that work as transporters that dissipate ion gradients.
  • Some form pores (channels) in the membrane through which ions can diffuse in or out of the cell.
    • e.g., Gramicidin A is a peptide antibiotic with alternating D- and L-amino acids that forms a channel large enough for protons, Na⁺ and K⁺ ions to pass through, but is blocked by Ca²⁺ (gramicidin)
  • Other ionophores serve as mobile carriers
    • e.g., Valinomycin, another antibiotic, is a cyclic depsipeptide (has some ester linkages as well as peptide bonds) with both D- and L-amino acids, that specifically binds K⁺ ions, and diffuses randomly from one side of membrane to the other, binding K⁺ where its concentration is higher, and releasing it where its concentration is lower. (valinomycin)
    • Monensin is a similar compound that's specific for Na⁺ ions.
  • Both types of ionophores dissipate ion gradients which are essential for cellular function, and thus are poisons.
  • Ionophores that are specific for infectious microorganisms can serve as antibiotics (e.g., gramicidin and valinomycin).
    
    
• Protein transporters
  • similar to enzymes in several respects:
    • specifity -- bind "substrate" (solute) with multiple noncovalent interactions
    • increase rate of approach to equilibrium (condition where C₁ = C₂) but don't change position of equilibrium
• Why would passage of a polar/hydrophilic solute across a membrane unassisted be SLOW?

Fig. 12-23 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Energy changes accompanying passage of a hydrophilic solute across a membrane (a) Simple diffusion: removal of the hydration shell is highly endergonic (DG > 0), and energy of activation (DG‡ ) for diffusion through bilayer is very high. (b) Transporter protein reduces DG‡ for transmembrane diffusion of solute by forming noncovalent interactions with dehydrated solute to replace hydrogen bonding with H2O (negative DGbinding counterbalances positive DGdehydration), and providing a hydrophilic transmembrane passageway (alternative pathway to cross lipid bilayer without having to interact with hydrophobic membrane core)

• some examples of protein transporters:
  • aquaporins (AQPs):
    • Peter Agre (Johns Hopkins School of Medicine) shared 2003 Nobel Prize in Chemistry for his work on aquaporins (PDF of news article in Science, 17 Oct. 2003)(PDF of 2002 Agre review article on aquaporin structure and function)
    • proteins permitting rapid movement of water across plasma membranes in specialized tissues like erythrocytes; cells of proximal renal tubule cells (function includes reabsorption of H2O during urine formation); and vacuolar membranes of plant cells (osmotic movement of water into vacuoles to maintain turgor pressure)
    • do not permit passage of ions or other small solutes
    • proposed topology (3-D arrangement in membrane) of AQP-1, in Fig. 12-24 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000)
      • (a) Each monomer is thought to have 6 transmembrane a helices
      • (b) Channel through membrane formed by 4 monomers, with hydrophilic side chains surrounding the central channel
      • NOTE: The recent high-resolution X-ray structure (Sui et al., Nature 414, 872-878, 2001 [PDF]) (see also review article PDF) suggests a channel within each monomer, NOT the central channel formed by 4 monomers in model in Fig. 12-24 from textbook shown below.

Porins found in outer membranes of gram-negative bacteria and outer membranes of mitochondria and chloroplasts Fig. 11-28 from Voet & Voet, Biochemistry, 2nd ed., 1995: E. coli OmpF protein allows certain solutes to pass through membrane, but only up to M.W. about 600 due to a loop of protein that partly blocks the channel. (a) ribbon diagram of monomer (16-stranded antiparallel b barrel, with amphipathic b sheet, hydrophilic R groups facing channel and hydrophobic R groups facing other monomers and lipid bilayer) (b) Ca backbones of all 3 subunits of trimer, viewed about 30o from trimeric protein's 3-fold axis of symmetry, showing the pore through each subunit (c) space-filling model of trimer shown perpendicular to 3-fold axis (N atoms blue, O atoms red, C atoms yellow, except aromatic side chain C atoms are white, forming hydrophobic band in contact with lipid core of bacterial outer membrane) (exterior of cell at top in parts (a) and (c) (porin).

• family of glucose transporters in various tissues (GluT1, GluT2, etc.)
  • increase rate of glucose transport, but only facilitate its movement DOWN its concentration gradient
  • Erythrocytes depend on constant supply of glucose from blood plasma, where [Glc] = ~4.5-5 mM, to use as energy source (fuel) via glycolysis
  • GluT1 increases rate of glucose diffusion across membrane by factor of about 50,000.
  • Fig. 12-25 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Proposed structure of GluT1

3-D structure not yet determined, but proposed structure (here) has multiple (12) transmembrane amphipathic a-helices that assemble to suuround a channel -- hydrophobic R groups on outer sides of helices facing bilayer, hydrophilic sides lining an aqueous channel, with many opportunities for hydrogen bonding with glucose passing through the transporter

• Fig. 12-26 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Kinetics of glucose transport into erythrocytes. K_t is analogous to K_m, the Michaelis constant for an enzyme: K_t = solute concentration that gives 1/2 the maximal rate of transport..
  • 3 hallmarks of facilitated diffusion:
    • high rate of diffusion down a concentration gradient
    • saturability
    • specificity

Fig. 12-27 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Model for glucose transport into erythrocytes by GluT1. Transporter exists in 2 conformations, T1 with glucose binding site exposed on outer surface of plasma membrane, and T2, with binding site exposed on inner surface. D-Glc binding on outside to stereospecific binding site on T1 conformation triggers conformational change to T2. Glc is released into cytosol, triggering conformational change back to T1, ready to pick up another glucose from the outside. Process is fully reversible, and as [S]in approaches [S]out, rates of entry and exit become equal. Kt(D-Glc) << Kt for epimers D-Man or D-Gal, and <<< Kt(L-Glc) blood plasma [Glc] ~4.5-5 mM, much greater than Kt (D-Glc) (~1.5 mM), so GluT1 operates near Vmax. Other tissues have other Glc transporters, with different Kt values relative to normal blood [Glc], appropriate for their physiological functions. Kt for GluT2 (liver) is ~66 mM; when liver breaks down glycogen and intracellular [Glc] increases above 5 mM (which is far below Kt for GluT2), GluT2 Vo increases linearly with increase in [Glc], to pass Glc OUT of cell to replenish blood glucose.

• Gated channels, for example ion channels
  • passive transport -- ions flow DOWN their concentration gradients
  • highly selective for particular ions -- specificity, though it may not be absolute
  • 2 conformational states, open and closed
    • open <==> closed transition regulated by some signal -- channels are either
      • ligand-gated (a chemical signal, e.g. acetylcholine, binds to channel to bring about conformational change), or
      • voltage-gated (electrical potential changes cause conformational change that opens channel for ions to rush in "down" their concentration gradient, as in propagation of nerve impulses (action potentials)).
    • Open states often spontaneously convert back to closed states, a kind of built-in "timer" that determines duration of ion flow.
  • Background: Animal cells maintain a steep gradient of Na⁺ and K⁺ ions across their plasma membranes: [Na⁺]_OUT >>> [Na⁺]_IN, while [K⁺]_IN >> [K⁺]_OUT.
    • We say membranes with this large ion concentration/charge gradient are in a state of polarization.
    • Generating and maintaining this transmembrane ion concentration gradient costs the cell a LOT of energy (see active transport, Na⁺-K⁺ ATPase, below).
      
      
  • Acetylcholine receptor: a ligand-gated ion channel

Schematic representation of a synapse (Fig. 13.14 from Berg, Tymoczko & Stryer, Biochemistry, 5th ed., 2001) Nerve impulse traveling down axon of a nerve fiber arrives at a synapse and triggers release of acetylcholine (a neurotransmitter, the acetic acid ester of the alcohol choline) from synaptic vesicles of first neuron into space between first neuron and next neuron. Acetylcholine binds to acetylcholine receptors on membrane of 2nd neuron (the "postsynaptic membrane") and causes the opening in postsynaptic membrane (2nd neuron) of a single kind of channel that lets Na+ ions rush IN (down their concentration gradient), triggering an action potential, and lets K+ ions rush OUT (down their concentration gradient).

• Nicotinic acetylcholine receptors
  • found in plasma membrane of muscle cells (myocytes), where they receive electrical signal from motor neuron
  • binding of actetylcholine (released from neuron) to muscle cell acetylcholine receptor triggers conformational change (opens channel), letting Na⁺, K⁺, and Ca²⁺ pass through, but no other cations or any anions.
• Fig. 12-39 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Structure of the acetylcholine receptor ion channel
  • 5 subunits (a₂bgd), each with 4 transmembrane (TM) helices. 2 acetylcholine binding sites, 1 on extracellular side of each a subunit.

5 subunits arranged around central TM channel, lined with polar sides of amphipathic M2 helices (other helices mainly hydrophobic) top & bottom of channel have rings of negatively charged residues middle of channel (near middle of bilayer) has 5 Leu residues (1 from each subunit's M2 helix) protruding into channel, constricting it so diameter is too small for Na+, K+, and Ca2+ to pass through unless "gate" opens.

Top view of cross section through center of M2 helices, 1 from each subunit (constriction) shows blocking of channel by bulky Leu side chains When both acetylcholine binding sites (one on each a subunit) are occupied, conformational change makes M2 helices twist slightly, rotating Leu side chains away from channel, and "replacing" them with small polar residues. This gating mechanism opens channel, allowing passage of Na+, K+, or Ca2+ ions. molecular mechanism of "desensitization" (closing channel even if acetylcholine is still present) not well understood

• Sodium, potassium and calcium channels -- voltage-gated ion channels
  • These eukaryotic proteins seem to be structurally related.
  • no high resolution 3-D structures yet
  • From amino acid sequences, Na⁺ and Ca²⁺ channels seem to be homologous (common evolutionary origin).
    • Both are long polypeptides with 4 internal repeats having similar amino acid sequences, suggesting that an ancestral gene underwent several internal duplication events.
    • Each of these internal units (homology units) contains 5 hydrophobic segments presumed to be transmembrane a helices, and a 6th segment with several positive charges that's thought to be the voltage sensor in the structure, but also to be a transmembrane helix.
  • K⁺ channel is shorter -- it seems to be homologous to a single one of the repeated units of the sodium channel; instead of having 4 internally repeated units in a single polypeptide chain, the K⁺ channel has 4 individual subunits that come together to form a functional channel.
    
    
  • bacterial (prokaryotic) potassium channel
    • high-resolution structure recently determined [PDF of original paper] (Rod MacKinnon, now at Rockefeller Univ., shared the 2003 Nobel Prize in Chemistry for work on the potassium channel -- PDF of Science 17 Oct. 2003 news article.)
      • homotetramer -- 4 identical subunits, each of which includes just 2 membrane-spanning a helices, corresponding to just the last 2 segments of the much larger eukaryotic ion channels.
      • 3rd helix on each subunit contributes to pore region
    • Fig. 12-38 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Structure of the K⁺ channel of Streptomyces lividans
    • Chime routine for K+ channel structure
    • 8 TM helices (2 from each subunit) form a cone with wide end toward extracellular space.
    • Inner helices line channel, and outer helices interact with lipid bilayer.
    • Inner channel lining helices responsible for selectivity filter.
    • negatively charged residues at channel entryways near membrane surfaces (both sides) to increase the local concentration of cations

• Selectivity filter:
  • Ion path begins (on inner surface) as wide, water-filled channel, so cations can enter with hydration sphere intact.
  • Partway through membrane, channel narrows, so waters of hydration have to come off.
  • Carbonyl O atoms from protein backbone in selectivity filter region replace water molecules, binding to K⁺, with a series of perfect coordination shells through which K⁺ can move.
  • Na⁺ ions can't interact favorably with the filter (they're too small).
  • K⁺ ions pass through the channel in "single file", at a rate approaching the diffusion limit.
  • Open this link [html]][PDF] for a more detailed discussion of structure and selectivity mechanism.

• UNIPORT: systems that transport only one solute.
• COTRANSPORT: (obligatory) transport of 2 solutes at the same time
  • Symport: the cotransported solutes go in the same direction
  • Antiport: the cotransported solutes go in opposite directions
    

Fig. 12-29 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): 3 general classes of transport systems Terms apply to both passive and active transport systems.

• Active transport: allows cells to transport materials against a concentration gradient.
  • Moving solutes against a concentration gradient requires free energy coupling to a favorable process, such as hydrolysis of ATP, or co-transport of another solute "down" its concentration gradient.

Fig. 12-30 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Primary vs. Secondary Active Transport primary active transport: "uphill" solute transport directly coupled to an exergonic chemical reaction, e.g., ATP hydrolysis. secondary active transport: "uphill" solute transport is coupled to "downhill" transport of a different solute whose gradient was established (is maintained) by primary active transport.

• Transport ATPases couple ion transport to ATP hydrolysis or ATP synthesis -- 3 types of transport ATPases:
  • P-type ATPases: ATP-driven cation transporters that are reversibly phosphorylated by ATP as part of transport mechanism; inhibited by vanadate, a phosphate analog. Examples:
    • Na⁺-K⁺ ATPase (antiporter in animal cell plasma membranes, maintaining essential electrochemical gradient of Na⁺ and K⁺ ions across cell membrane -- see below)
    • Ca²⁺ ATPase (uniporter in animal cell plasma membranes, maintaining low cytosolic Ca²⁺)
    • H⁺K⁺ ATPase (symporter in stomach parietal cell plasma membranes -- exports K⁺ and protons, acidifying stomach contents)
  • V-type ATPases: proton pumps responsible for acidifying contents of inracellular compartments in many organisms, e.g., plant vacuoles and animal cell lysosomes
    • not reversibly phosphorylated/dephosphorylated as part of the mechanism, not inhibited by vanadate
• F-type ATPases: central role in energy transducing reactions in bacteria, mitochondria, and chloroplasts -- convert the potential energy of a proton electrochemical gradient into chemical bond energy, running ATP "hydrolysis" BACKWARDS --> ATP SYNTHESIS
  • Proton gradient established by chemical energy of oxidation reactions (electron transport in the membranes) drives proton flow back down the chemical (and charge) gradient, into bacterial cells or into mitochondrial matrix or into stroma of chloroplast, and the proton flow drives ATP synthesis from ADP + P_i.
  • If there's no proton gradient, or enzyme is uncoupled from it, enzyme hydrolyzes ATP.
    
  • Anatomy of proton pumping
    • Energy needed to produce ATP comes from oxidation of fuels (food). 
    • Ultimately the energy comes from the reduction of oxygen to water, which is carried out in the electron transport chain, a series of linked oxidation-reduction enzymes found in the inner mitochondrial membrane (or in the inner membrane of bacterial cells). 
    • During passage of electrons along this chain, protons are pumped across the inner mitochondrial membrane, generating a proton gradient that is the driving force for the synthesis of ATP.  
    • One of the components of the electron transfer chain is cytochrome c oxidase, a protein whose structure has been determined and a proposal has been made for the location (channel) through which the proton moves across the membrane.
    • The channel contains a hydrogen-bonded water network that spans the membrane and through which a proton could move across the membrane. The channel also includes the heme group involved in electron transfer.  
    • This chime script shows how this might work (Cytochrome oxidase).
      
      
• Ion pumps couple ATP hydrolysis to ion transport -- example of a P-type ATPase
  • Na⁺-K⁺ pump of animal cell plasma membranes (also called the Na⁺-K⁺ ATPase) maintains high intracellular concentration of K⁺ and low intracellular concentration of Na⁺.
    • pumps Na⁺ out of the cell against a concentration gradient and takes K⁺ into the cell against a concentration gradient.
    • The Na⁺ and K+ gradients and the electrical potential (charge gradient) are used to drive OTHER essential transport processes.
    • The energetics are described here.
      
      
  • Fig. 12-33 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Na⁺K⁺ATPase
    • a very important system in animals -- about 25% of the total energy consumption of a human at rest is invested in this transport system, maintaining the Na⁺ and K⁺ gradients and electrical potential across plasma membranes.

Pump driven by ATP hydrolysis mechanism (see also Fig. 12-34 in Nelson & Cox) involves reversible phosphorylation of an Asp residue on the enzyme, and 2 conformations of the enzyme: Conformation I: high affinity for Na+, low affinity for K+, "open" to inside of cell. Conformation II: low affinity for Na+, high affinity for K+, "open" to outside of cell. Transfer of phosphate group from ATP to enzyme (releasing ADP as a product) triggers conformational change in enzyme -- phosphorylated enzyme predominantly in conformation II. Hydrolysis of phosphate group from the enzyme triggers return to original conformation (I).

Mechanism of the Na+-K+ pump, starting on upper left (like Nelson & Cox Fig. 12-34) Unphosphorylated enzyme (EnzI) binds 3 Na+ from inside cell [EnzI •3Na+] is phosphorylated (on Asp residue), generating second conformation. EnzII-P releases 3 Na+ ions outside and binds 2 K+ ions from outside cell. [EnzII-P •2K+] has phosphate hydrolyzed off (inside cell). Unphosphorylated enzyme switches to conformation I (EnzI), releasing 2K+ inside cell, now ready to bind 3 Na+ again.

This animation shows operation of the pump. Upper side = outside of cell; lower side = cytosol. The colored ball represents ATP; the three yellow diamonds Na+ and the two red diamonds K+.   From The Virtual Cell Web Page

• Ion gradients (and electrical potentials/gradients) provide the energy for SECONDARY ACTIVE TRANSPORT.
  • (Ionophores dissipate ion gradients and thus are poisons, or antibiotics for microorganisms.)
  • COTRANSPORT processes that utilize a favorable gradient for one compound to drive the uptake of a second compound.
  • Sodium-glucose cotransport across apical surface of intestinal epithelial cells is one example, accumulating Glc in cell against its concentration gradient
    • Fig. 12-36 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Glucose transport in intestinal epithelial cells

Glucose import from intestine made possible by Na+-K+ ATPase (shown on right side of cell), which generates/maintains both high Na+ concentration outside cell and charge gradient (electrical potential) that both favor Na+ import through Na+-glucose symporter. Permits epithelial cells to concentrate glucose from intestine to 30,000x the intestinal concentration Resulting high concentration of glucose within cell passes "down" its concentration gradient through basal surface of cell into blood via GluT2 transporter (facilitated diffusion, uniport system).

• Many other secondary active transport systems are known, especially in mitochondrial membrane.
• Other examples of secondary active transport:
  • Sodium-calcium exchanger of animal cell membranes: antiporter that couples downhill flow of 3 Na⁺ into cell with uphill extrusion of 1 Ca²⁺ out of the cell (Na⁺ gradient was generated by the Na⁺-K⁺ ATPase.)
  • Lactose permease of E. coli: symporter that uses H⁺ gradient across E. coli membrane (generated by fuel oxidation and electron transport) to let protons flow down their concentration gradient back into the cell, bringing lactose into the cell against a concentration gradient (see Fig. 12-35 in Nelson & Cox, Lehninger Principles). This perspective/commentary from Science 301, 603-4 (1 Aug. '03) (PDF) discusses the crystal structure and the function of lactose permease (lacY), with references.

Fig. 12-43 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Types of transport (summary)

Gaseous anesthetics

Halothane, CHBrClCF3, is a gaseous anesthetic. Such anesthetics are secreted from the body unchanged. potency of these anesthetics directly proportional to their solubility in lipid solvents It seems likely that these compounds act by dissolving in the hydrocarbon portion of the lipid bilayer. Addition of these molecules to the hydrocarbon core would alter properties of the bilayer, e.g., fluidity (like adding more cholesterol). The altered membrane properties probably affect ion transport and nerve conduction.

Inhibiting the Na+-K+-ATPase makes the heart contract more strongly. Digitalis, which is prepared from the purple foxglove (Digitalis purpurea), is a cardiac glycoside. Active ingredient is digitoxin, shown below.  Digitoxin (see below) contains three sugar residues (purple), which account for the glycoside in the name.  The other part is the aglycon (blue), which resembles a sterol.  The aglycon dissolves the membrane and the glycoside helps to improve water solubility. Digitoxin inhibits the Na+-K+ ATPase transport system, leading to a loss of K+ from the heart cells and an increase of Na+ in heart cells.  The increased Na+ activates a Na+-Ca2+ pump that exchanges intracellular Na+ for extracellular Ca2+. The increase in intracellular Ca2+ enhances myocardial contraction. This causes more force to be generated without increased oxygen consumption.  Digitoxin also slows the heart rate, which allows more filling of the heart and improves cardiac output, so it is used to treat congestive heart failure. Another cardiac glycoside, ouabain, a product of the East African Ouabio tree, has long been used as an arrow poison -- it's a potent and specific inhibitor of the Na+-K+ ATPase.