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Patch clamp connects an electrode to a small area of cell membrane through a solution-filled patch pipette. A gigaohm seal around the rim makes tiny electric currents through ion channels distinguishable from seal leak current. The beautiful change of scale is from a population's average response to individual opening and closing events in single-channel recording.

Separate two questions. The configuration determines which cell membrane is accessible: an intact patch in cell-attached recording, an excised inside-out patch or outside-out patch, or intracellular access in whole-cell recording. The recording mode determines what is commanded and what is observed: voltage clamp commands an electric potential difference and measures electric current; current clamp commands electric current and measures membrane potential. Whole-cell recording supports both modes. A patch can contain several ion channels; a small recording area does not establish that only one is present.

The 1976 article Single-channel currents recorded from membrane of denervated frog muscle fibres describes an extracellular fire-polished pipette with a $3$–$5\mu \mathrm{m}$ opening and $2$–$5\mathrm{M\Omega }$ electrical resistance. It contained saline and a channel-activating compound. Two separate intracellular electrodes supplied local voltage clamp of the muscle fibre; the patch amplifier measured local electric current. Cooling to $6$–$8{}^{\circ }\mathrm{C}$ and hyperpolarization helped resolve elementary events. Figure 2 shows step-like pulses with a $200\mathrm{Hz}$ filter at $-120\mathrm{mV}$ and $8{}^{\circ }\mathrm{C}$. Discrete amplitudes and overlapping events supported individual ion channel openings rather than a smoothly varying population response. This was neither whole-cell recording through the patch pipette nor current clamp. The specialized conditions improved visibility but limit generalization to warmer preparations; filtering can conceal brief openings.^[ref]

For a new single-channel recording experiment, useful controls include a matched recording without the activating compound, controlled membrane potential, repeated seal tests, and an explicitly stated filter frequency response. These are proposed controls, not claims that every one was performed in that 1976 figure. Changing membrane potential tests the single-channel current-voltage relation; changing the recording filter tests whether a short pulse's apparent amplitude is an instrument artifact. A flat baseline establishes neither an absence of ion channels nor an absence of very brief events.

Phospholipids are lipids containing a phosphate group as part of their structure linked by covalent bonds. The familiar membrane-forming phospholipids are amphiphilic: a hydrophilic head region with chemical polarity coexists with a hydrophobic, largely nonpolar hydrocarbon region. These descriptions refer to different parts of the same molecule, not to two separate substances. See IUPAC Gold Book: phospholipids and IUPAC Gold Book: amphiphilic.

A typical two-chain glycerophospholipid provides a useful example: a glycerol scaffold carries two fatty acid-derived acyl groups through ester linkages, plus a phosphate-containing head region. Phosphatidylcholine is one example. This scaffold describes an important subclass, rather than all phospholipids: sphingomyelin has a different backbone, and even glycerophospholipids need not all have two acyl groups. See IUPAC–IUB, Nomenclature of Lipids (1976), Lip-1.5 and Lip-2.1–2.6.

Polar does not mean negatively charged overall. At near-neutral pH, phosphatidylcholine is zwitterionic: its phosphate region carries negative electric charge and its choline region positive electric charge, with zero net electric charge for the molecule. Counting those opposite charges gives $(-1)+(+1)=0$; it does not remove their local interactions with water. See Lodish et al., Molecular Cell Biology: membrane lipids.

In a lipid bilayer, two membrane leaflets orient their hydrophilic heads toward the water on either side and their hydrophobic chains toward the shared interior. The hydrophobic effect helps explain this organization through the free energy of the water and lipids together. It is not a special repulsive chemical bond between chains and water. Which organization is favored also depends on molecular geometry, temperature, concentration, and the surrounding chemical solution; a phospholipid label alone does not guarantee a lipid bilayer. See Alberts et al., Molecular Biology of the Cell: the lipid bilayer.

This organization supplies a flexible barrier for compartments. A fluid lipid bilayer allows lipids to undergo diffusion within each membrane leaflet; barrier function therefore coexists with motion of molecules, as in the fluid mosaic model. It is not completely impermeable: small nonpolar molecules such as molecular oxygen and carbon dioxide cross much more readily than ions. In a cell membrane, ion channels and other membrane transport proteins provide selective routes; the existing membrane transport article explains their driving forces. See Alberts et al.: principles of membrane transport.

In 1925, E. Gorter and F. Grendel extracted lipids from red blood cells and compared the surface area of a one-molecule-thick film on water with the estimated total surface area of the red blood cells. Their table gave ratios near two, supporting a two-layer covering; they also proposed heads facing the aqueous surroundings on both sides. The inference depends on recovering the relevant lipids, estimating the red blood cell surface area correctly, and comparing compatible packing in the film and the cell membrane. It was indirect evidence, not an image of the lipid bilayer. The paper itself notes possible losses during evaporation. See Gorter and Grendel, On Bimolecular Layers of Lipoids on the Chromocytes of the Blood, Journal of Experimental Medicine 41 (1925), 439–443.

A biochemical receptor is a protein that recognizes a signal and couples its detection to a biological effect. Its binding partner is a ligand; recognition depends on compatible shape and chemical interactions at a binding site within the protein structure. Specificity is selective recognition, not a guarantee that only one ligand can bind. Binding also need not activate the receptor: a competing ligand may occupy it while preventing activation by another ligand. See Alberts et al., Molecular Biology of the Cell, 4th edition: protein binding and specificity.

Compare a cell-surface receptor, accessible to an extracellular ligand, with an intracellular receptor, whose ligand must reach the interior. A cell-surface receptor can detect a hydrophilic ligand without transporting it through the cell membrane. In contrast, some membrane-permeable signals reach intracellular receptors that regulate gene expression. Location and downstream coupling are separate distinctions: an ionotropic receptor directly gates an ion channel, whereas a metabotropic receptor works through intracellular signal transduction. See Clark, Douglas and Choi, Biology 2e, 9.1: receptor locations and mechanisms.

Receptor binding occupancy quantifies recognition separately from response. A dissociation constant measures binding in a specified equilibrium model; it does not by itself predict the cellular effect. This separation is useful when comparing signals that bind equally well but produce different responses, or when interpreting a binding experiment alongside a functional measurement.

A reversal potential $E_{\mathrm{rev}}$ is a membrane potential at which a specified open ion channel, or specified combination of ion channels, carries zero net electric current, with the surrounding conditions fixed; the electric current changes sign across that voltage. Specifying which current matters: an individual ion contribution and a sum of several contributions can reverse at different voltages. Zero net electric current does not mean that all ions have stopped moving. See Purves et al., Neuroscience, 2nd edition (2001): reversal of a mixed-ion channel current.

Throughout these examples, membrane potential is $V=V_{\mathrm{inside}}-V_{\mathrm{outside}}$, and conventional current is inward-positive. Positive electric current corresponds to net positive electric charge entering or net negative electric charge leaving. Negative electric current corresponds to the reverse charge transfer. A convenient Ohmic approximation iswhere $g$ is the available electrical conductance. For fixed $g>0$, $V<E_{\mathrm{rev}}$ gives positive electric current, $V=E_{\mathrm{rev}}$ gives zero, and $V>E_{\mathrm{rev}}$ gives negative electric current; the line has slope $-g$. If $g=0$, the modeled pathway carries zero electric current at every voltage: closing it does not locate its reversal potential. 3.1 Synapses (§3.1: conductance-based synaptic current) uses outward-positive $g(V-E)$; the formula here reverses that sign to match this wiki's inward-positive convention.

For the stipulated single-pathway example from ion channel, $E_{\mathrm{rev}}=-80\mathrm{mV}$ and $g=10\mathrm{nS}$ giveThe open ion channel carries zero net electric current at $-80\mathrm{mV}$ even though $g$ remains positive. Near that point a change of membrane potential changes the electric current, which is why zero current at one voltage does not make an open pathway electrically irrelevant; see shunting inhibition.

For an ion channel passing only one ion species by passive transport, its reversal potential can equal that species' Nernst equilibrium potential, where the chemical and electrical contributions to electrochemical potential balance. At that thermodynamic equilibrium, passage in both directions can continue with no net transport. For an ion channel admitting several ion species, opposing contributions can cancel while each species continues to have net transport. Such a reversal potential is not generally any one species' Nernst equilibrium potential. See the Purves reference above.

To work out that cancellation explicitly, put two Ohmic ion channel populations across the same cell membrane. Stipulate constant electrical conductances and fixed reversal potentials:The potassium and sodium contributions add because both pathways experience the same membrane potential:Thus $I_{\mathrm{total}}=12\mathrm{nS}(E_{\mathrm{eff}}-V)$. This weighted mean follows simply by expanding and regrouping the two current terms; it assumes additive Ohmic contributions and a positive total electrical conductance. At $V=E_{\mathrm{eff}}$, the inward-positive individual electric currents areThe potassium contribution is outward and the sodium contribution inward. Equal and opposite electric currents give $I_{\mathrm{total}}=0$; neither pathway has stopped transporting its ions. The calculation treats two distinct pathways. Applying it to one mixed-species ion channel would additionally require a justified decomposition into independent Ohmic contributions; a general mixed-channel reversal potential cannot be obtained by assuming those hypotheses silently.

This is an instantaneous balance of the specified passive electric currents. It would be the stationary voltage of a passive capacitance model containing only these constant pathways and no applied electric current, but it is not a complete prediction of a living cell's resting membrane potential. Other electric currents, voltage-dependent gating, and pumps involved in active transport can matter. Pumps that transfer net electric charge are electrogenic and contribute their own electric current. See Purves et al.: functional properties of the sodium/potassium pump.

The toy model holds ion concentrations and therefore the stipulated reversal potentials fixed. Continuing inward sodium and outward potassium transport would change finite reservoirs unless active transport or external control maintained them. Transport can be a small fraction of the reservoir's ions over a short interval, making fixed concentrations a useful approximation; it is not a claim that the reservoirs never change. See Gerstner et al., Neuronal Dynamics (2014), §2.1: equilibrium potentials, channel currents and maintained gradients.

A reversal potential makes the effect of opening an ion channel predictable from the present membrane potential. The same open pathway can carry inward or outward electric current as $V$ crosses its reversal potential. The two-pathway example reveals a particularly useful distinction: zero net charge transfer can coexist with continuing exchange of different substances. That distinction connects membrane transport to electric current measurements without mistaking electrical balance for thermodynamic equilibrium.

Seal leak current bypasses the membrane patch through an imperfect seal. For an ideal ohmic seal to a zero-voltage bath, $I_{\mathrm{seal}}=V_p/R_{\mathrm{seal}}$, positive from pipette to bath. At $|V_p|=50\mathrm{mV}$ and $R_{\mathrm{seal}}=1\mathrm{G\Omega }$ its magnitude is $50\mathrm{pA}$, far larger than the synthetic $0.8\mathrm{pA}$ single-channel step. A stable baseline can be subtracted, but changing leakage can mimic a biological response. Intrinsic membrane leak through ion channels is distinct from this bypass: interpreting both as the same electrical conductance obscures whether the biological cell or the seal changed.

Shunting inhibition is suppression of another input's effect through increased synaptic conductance: opening additional ion channels lowers effective electrical resistance, reducing the voltage response to a given added electric current. When the added reversal potential equals the resting membrane potential, there can be no voltage change at rest and still be inhibition of a simultaneous input. See 1.4 Limitations of the Leaky Integrate-and-Fire Model.

Use the passive synaptic potential model below with leak $g_L=10\mathrm{nS}$, $E_L=-65\mathrm{mV}$ and capacitance $C=200\mathrm{pF}$. A sustained inward test electric current of $I_{\mathrm{ext}}=100\mathrm{pA}$ alone gives a steady voltage increase of $I_{\mathrm{ext}}/g_L=10\mathrm{mV}$, so $V_{\infty }=-55\mathrm{mV}$. Effective electrical resistance is $100\mathrm{M\Omega }$ and the time constant is $20\mathrm{ms}$.

Now hold a shunting conductance $g_i=20\mathrm{nS}$ open with $E_i=E_L=-65\mathrm{mV}$. With no test electric current, rest stays at $-65\mathrm{mV}$. With the same $100\mathrm{pA}$ test electric current, total conductance becomes $30\mathrm{nS}$, so the steady voltage increase is only $100/30\simeq 3.333\mathrm{mV}$: $V_{\infty }\simeq -61.667\mathrm{mV}$. Effective electrical resistance is $33.333\mathrm{M\Omega }$ and the time constant is $200/30\simeq 6.667\mathrm{ms}$. A faster response can therefore be smaller. At the original rest the shunting electric current is zero; at $V=-55\mathrm{mV}$ it is $20(-65+55)=-200\mathrm{pA}$, opposing the voltage excursion.

The factor of three reduction applies to this constant-electric current, constant-conductance example. A finite pulse, conductance-driven input or spatially extended dendrite need not have the same reduction. The interesting feature is conditional action: the shunt can leave a quiet neuron's voltage unchanged yet reshape its response when another input arrives. A model that represents all inhibition as a fixed outward electric current misses this behavior.

Signal transduction converts a detected signal into a change inside a biological cell. For chemical signals, distinguish reception by a receptor, intracellular signal transduction, and the response: altered gene expression, enzyme activity or ion channel opening, for example. A cell-surface receptor can relay a ligand's presence across a cell membrane without the ligand entering the cytoplasm. Thus a hydrophilic signal need not cross the membrane to influence the interior. See Clark, Douglas and Choi, Biology 2e, 9.2: intracellular signal propagation.

For a computed example of possible signal amplification, suppose one activated receptor activates five relay proteins, and each relay activates twenty target proteins during a chosen interval. If the targets are distinct and available, $1\times 5\times 20=100$ targets are activated. Those assumed counts illustrate multiplication, not a measured pathway or a universal gain. Actual signal transduction can branch, saturate or inhibit activity. Changes in gene expression and changes in existing enzyme activity are different responses. See Clark, Douglas and Choi, Biology 2e, 9.3: cellular responses.

Signal amplification, signaling feedback and signaling adaptation are possible properties of signal transduction, rather than requirements of every cascade. Intracellular relays can use proteins or second messengers; different biological cells can interpret the same ligand differently because they contain different receptors and relay machinery. The useful and striking idea is that recognition and response are separable: an extracellular chemical message can control many internal tasks without itself performing those tasks. See General Principles of Cell Communication.

An original experimental route to this separation appears in T. W. Rall and Earl W. Sutherland's 1958 work on cAMP. They described a heat-stable factor formed from ATP in separated biological cell preparations; it affected enzyme activity in other preparations where the initiating chemical signals had no direct effect. This helped distinguish an initial signal from a molecule carrying its effect to another target. ^[ref]

For an ideal open ion channel with constant electrical conductance $g$, membrane potential $V$ and reversal potential $E_{\mathrm{rev}}$, define outward electric current as positive:This is an Ohm's law model of the open state, not a universal channel law or a rule for opening probability. In the synthetic figure, $g=10\mathrm{pS}$ and $E_{\mathrm{rev}}=0\mathrm{mV}$. Because $1\mathrm{pS}\cdot 1\mathrm{mV}=10^{-3}\mathrm{pA}$, the open-state electric currents at $-80$ and $-40\mathrm{mV}$ are $-0.8$ and $-0.4\mathrm{pA}$. Zero electric current at the reversal potential does not imply a closed ion channel. Real ion channels can have nonlinear responses, so the straight line is an explicit idealization.