Resting membrane potential (RMP) refers to the transmembrane potential (i.e., the potential difference across the cell membrane) in the steady (unexcited) state. RMP is present across all cells (see below).
A summary of the genesis of resting membrane potential.
- The cell membrane is impermeable to organic anions and proteins present in ICF.
- In neurons for example, in the resting state, the cell membrane is quite permeable to K, (about 50 times more permeable to K than Na). K exits the cell down its concentration gradient, making the inside of the cell negative with respect to exterior.
- Charge separation occurs across the membrane (a thin capacitor) leaving the inside of the membrane negative with respect to outside.
- Additionally, the Na-K ATPase mechanism contributes a small extent to making the inside of the cells negative.
Magnitude of RMP in different tissues
|Cell / tissue||Magnitude of RMP (inside negative)|
|Nerve cells||– 70 mV|
|Skeletal muscle||– 90 mV|
|GI smooth muscle||Variable; – 40 to – 60 mV|
|Cardiac muscle||– 90 mV|
|SA node||– 70 mV|
|Red blood cells||– 10 mV|
The two types of forces tending to drive ion flux across membranes are the electrical and chemical (concentration) gradients. Flux requires the membrane to be permeable to ions.
Equilibrium potential: the membrane potential at which net transmembrane flux of a particular ion is zero because the electrical gradient counterbalances the chemical gradient.
Example, Na flux across the membrane would stop when the membrane potential reaches + 60
mV. The equilibrium potential of an ion is calculated using the Nernst equation.
ENa = – 61 log [Na]i / [Na]o, where i and o refer to intra- and extracellular concentration of the ion in question.
ENa = – 61 log [10/140] = + 61 mV
Similarly, for K:
EK = – 61 log [K]i / [K]o
Normally, Ki = 140 mM, Ko = 5 mM EK = – 90 mV
Equilibrium potentials for various ions across nerve cell membranes:
|Ion||ICF (mM)||ECF (mM)||Equilibrium potential (mV)|
|Ca||100 nM||2.5||+ 130|
Excitability: The response to a ‘threshold stimulus’ with a propagated action potential.
The physiologic basis of excitability: High potassium permeability at rest (and therefore an RMP in the range of –50 to –90 mV), and presence of voltage gated Na channels are essential. Only nerve, neurons, and the three muscle types (skeletal, cardiac and smooth) are excitable. Other tissues are not.
What is the effect of hyperkalemia on RMP of cardiac muscle cells?
When plasma [K+] = 5 mM, the potassium equilibrium potential of cardiac muscle cells is minus 90 mV inside negative.
When plasma [K+] is raised to 10 mM, or when extracellular potassium in the vicinity of ischemic or injured myocardium increases to 10 mM, the potassium equilibrium potential in that zone becomes
EK = – 61 log [140/10] = – 70 mV
Thus hyperkalemia makes KEq less negative.
Since the resting membrane is much more permeable to K relative to Na, RMP is closer to EK. Thus, hyperkalemia makes RMP less negative; closer to threshold. The SA node has an RMP of -70 mV. In this situation, the injured myocardium would be expected to compete with SA node to pace the heart. This clearly increases the risk of cardiac arrhythmias.
Hypokalemia makes cells less excitable by making RMP more negative.
RMP is measured with microelectrodes, and it is calculated using the Goldman-Hodgkin-Katz equation. The RMP is affected by the conductance of all ions in a resting membrane. This is why RMP differs between tissues (-60 mV in neurons and -90 mV in skeletal muscle).
If the nerve is stimulated with the cathode (using a subthreshold stimulus), it produces small depolarizations (called catelectrotonic potentials). These small depolarizations are local responses;
i.e. they are not propagated through the nerve fiber. The stimulus that is just adequate to result in a propagated action potential is called threshold stimulus.
The membrane potential at which voltage gated Na-channels open all at once to result in a full fledged action potential is called firing level or threshold level and it is about -55 mV in nerve fibers. Within a millisecond of opening, Na channels get deactivated; i.e. close and cannot be opened until the membrane potential comes back down to firing level. On the other hand, voltage gated K channels open allowing rapid efflux of K. This repolarizes the membrane; i.e., brings it back to RMP.
Differences between local responses and action potentials:
Local responses (also called electrotonic potentials) may be depolarizing (also called catelectrotonic potentials) or hyperpolarizing (also called anelectrotonic potentials). Excitatory postsynaptic potentials (EPSP) and miniature motor end plate potentials (MEPP) are examples of catelectrotonic responses. Inhibitory postsynaptic potentials (IPSP) are anelectrotonic
responses. Electrotonic potentials are graded responses (i.e. proportional to stimulus intensity) that occur with subthreshold stimuli, and their magnitude is typically a few mV. They undergo spatial and temporal summation. They are not propagated. In contrast, action potentials are propagated responses that occur with “threshold stimuli”. They are all-or-none; i.e., they occur with a constant size.
Excitability during various phases of the action potential:
Absolute refractoriness: No matter how strong the stimulus, a nerve (or muscle) is absolutely refractory to stimulation during the action potential until repolarization brings the membrane back to firing level. Within a millisecond of the beginning of the upstroke of the action potential, sodium channels are inactivated.
Relative refractory period: In this period, only a suprathreshold stimulus would trigger an action potential. The reason why a stronger stimulus is required for excitation is because the stimulus has to overwhelm the repolarizing current.
Supernormal phase: a weaker stimulus would trigger an action potential.
Subnormal phase: during afterhyperpolarization, a stronger stimulus would be required to bring the membrane to threshold.
Nerve and muscle may be excited using electrical, chemical or mechanical stimuli. For electrical stimuli, one may speak of the following stimulus parameters.
- Intensity: subthreshold, threshold, suprathreshold
- Duration: typically (in milliseconds)
- Frequency: 1-100 Hz
- Rise time: time in which stimulus intensity rises to its maximum value.
Threshold stimulus: The minimum stimulus intensity that elicits an action potential in an excitable tissue under a given set of conditions.
All-or-none law: If a stimulus is sufficiently intense as to bring the membrane to threshold, the
intensity of the stimulus has no bearing on the size of the action potential.
Physiologic basis of the all-or-none law: Action potential occurs only when the firing level (or threshold) is reached because the voltage-
gated sodium channels that allow a massive influx of Na open and cause the upstroke of the action potential occur only at the firing level.
Effect of stimulus intensity on electrical response of nerve and muscle (all-or-nothing):
|Stimulus Intensity||Electrical response in nerve / muscle|
|Subthreshold||No action potential|
|Suprathreshold||Action potential of the same strength|
The figure above depicts action potentials in a skeletal muscle fiber (top panel) and mechanical response (bottom panel) on the same time scale in skeletal muscle. Whereas the duration of the action potential is only about 5 ms, the duration of the mechanical response (contraction followed by relaxation) is much longer. Thus, it is possible to summate mechanical responses to successive stimulation of muscle. In cardiac muscle, this is not possible since the duration of absolute refractory period is much longer (about 200 ms at a heart rate of 75 bpm), and therefore relaxation commences before cardiac muscle is reexcitable.
Muscle twitch: A muscle twitch is contraction followed by relaxation occurring in response to a single stimulus.
Twitch duration = contraction time + relaxation time.
Twitch duration is quite variable and skeletal muscle is classified as fast or slow, depending upon twitch duration and other characteristics. The duration of muscle twitch in fast skeletal muscle fibers could be as short as 10 ms. In contrast, in slow skeletal muscle fibers, twitch duration is typically greater than 100 ms.
In cardiac muscle, when average heart rate is 75 beats per minute, average twitch duration is 800 ms; i.e., cardiac muscle is much slower than slow skeletal muscle. The twitch duration in the smooth muscle of sphincters is longer. Smooth muscle is thus the ‘slowest’ of the three muscle types.
Tetanizing stimulus frequency: With high frequency stimulation of skeletal muscle, it is possible to summate the effects of multiple stimuli and increase the force of muscle contraction.
Tetanus is the most forceful and sustained muscle contraction (i.e. with no relaxation in between). To tetanize skeletal muscle, it must be stimulated at a minimum frequency called the tetanizing frequency; this depends on the duration of contraction. The minimum stimulus frequency required for tetanizing the muscle is the reciprocal of the contraction period expressed in seconds.
For example, if the contraction period is 100 ms (i.e., 0.1 s), the tetanizing frequency is 1/0.1 = 10 Hz.
The figure above depicts the effect of an increase in the frequency of contraction of skeletal muscle on force. With increasing frequency of stimulation at a given intensity, the force of successive
contractions increase because of the beneficial effect of previous contractions and it is related to increased availablility of intracellular calcium for later contractions. This is called the staircase phenomenon, Treppe or Bowditch effect. With a decrease in frequency of stimulation, a gradual decrease in force of contraction is also observed.
Axoplasmic transport: This refers to transport of molecules in the cytoplasm of the axon. This is not to be confused with conduction of the nerve impulse, which is much faster.
Anterograde transport (i.e., from the cell bodies to axon terminals) is brought about by microtubules (kinesin and several other proteins are involved). Retrograde transport involves transport of a substance from nerve terminal toward the cell body. This is also achieved on microtubule tracks in the axoplasm. Viruses, some neurotrophins are taken up and transported this way.
|Axoplasmic transport||Speed (mm/day)|
|Fast anterograde transport||400|
|Slow anterograde transport||0.5–10|