BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 37. EXCITABLE MEMBRANES AND SENSORY SYSTEMS

The membranes of many Cells are capable of being excited by specific chemical or physical stimuli. The response of a nerve Cell axon membrane to an electrical stimulus, of a synapse to neurotransmitter release, of retinal rods to light, or of motile cells to attractant molecules—all these are reactions mediated by excitable complexes present in membranes. These and other processes mediated by excitable complexes share several key features.

1. The stimulus is perceived by a highly specific receptor protein, which is an integral component of the excitable membrane.

2. A specific stimulus induces a conformational change in the receptor, which in turn leads to an alteration in membrane permeability or The activity of a membrane-bound enzyme. In many cases, this results in a manifold Amplification of the response to specific stimuli.

3. Both the conformational shift and the resulting functional Changes in the receptor are reversible. Special mechanisms exist to return the receptor to its resting state and restore its excitability.

In this chapter, we will examine four types of excitable complexes, beginning with the sodium channel in nerve cell axon membranes; this voltage-gated channel is involved in the generation of action potentials in nerves. Next, we will turn to the chemically gated channel and examine how acetylcholine receptors mediate Nerve Impulse Conduction at certain synapses. We will then proceed to the retinal rods—exceptionally sensitive light detectors. Along the way, we will explore The Role of the photoreceptor protein rhodopsin in transducing light into a nerve signal. The final topic of this chapter is chemotaxis, the directed movement of cells toward attractants and away from repellents. In recent years, a wealth of new insights has been gained regarding the coupling of chemoreceptors to the motility apparatus in Bacteria.

37.1. Action Potentials Are Mediated by Transient Changes in Na⁺ and K⁺ Permeability

Nerve impulses are electrical signals generated by the flow of ions across The Plasma Membrane of Neurons. In a neuron, as in most cells, K⁺ is present at high concentrations and Na⁺ at low concentrations. The concentration gradients of these ions are generated by the (Na⁺ + K⁺)-pump (Section 36.2). In the resting state, the permeability of the nerve cell membrane to K⁺ is much higher than its permeability to Na⁺, and therefore the Membrane Potential is determined primarily by The ratio of intracellular to extracellular K⁺ concentration (Fig. 37.2, A). In unstimulated axons, the resting membrane potential is -60 mV, which is close to the value of -75 mV (the equilibrium K⁺ potential) corresponding to a membrane permeable exclusively to K⁺ ions. A nerve impulse, or Action Potential, is triggered when the membrane depolarizes beyond a threshold level (specifically, from -60 to -40 mV). Within a few milliseconds, the membrane potential becomes positive, reaching approximately +30 mV, before swinging back to negative values. This amplified depolarization propagates along the nerve until it reaches the nerve terminal. The Study of the giant squid axon played a pivotal role in unraveling The Nature of the action potential. Because this unusually large axon (about a millimeter in diameter) readily accommodates electrodes, it became a favorite model system for researchers.

Class="center">Fig. 37.1. Electron micrograph of a synapse

What is the mechanism underlying the action potential? Alan Hodgkin and Andrew Huxley conducted ingenious studies demonstrating that the action potential results from large, transient changes in the permeability of the axon membrane to Na⁺ and K⁺ ions (Fig. 37.2, B). First, the membrane permeability to Na⁺ changes. Depolarization of the membrane beyond the threshold level triggers the opening of Na⁺ channels. Driven by a steep transmembrane electrochemical concentration gradient for Na⁺, sodium ions rush into The Cell. This influx of Na⁺ further depolarizes the membrane, promoting the opening of even more Na⁺ channels. This positive feedback loop between depolarization and Na⁺ influx leads to very rapid and massive shifts in membrane potential: from -60 to +30 mV in just one millisecond. The influx ceases at approximately +30 mV because this value corresponds to the equilibrium Na⁺ potential. In other words, once this potential is reached, the thermodynamic driving force for Na⁺ entry vanishes. The Na⁺ channels close spontaneously, and by this time, K⁺ channels begin to open (Fig. 37.2, B). As a result, potassium ions flow out of the cell, and the membrane potential becomes negative once again. In about two milliseconds, the membrane potential drops to -75 mV, i.e., the equilibrium K⁺ potential. The resting level of -60 mV is restored a few milliseconds later as K⁺ conductance declines back to its unstimulated baseline. It must be emphasized that during an action potential, only a tiny fraction of Na⁺ and K⁺ ions crosses the plasma membrane—roughly one-millionth of the total amount of these ions inside the nerve cell. In other words, a single nerve impulse consumes an infinitesimally small fraction of the (Na⁺-K⁺) gradient. This highlights just how remarkably efficient the action potential is as a medium for long-distance signaling.

Fig. 37.2. An action potential arises from the depolarization of a nerve cell axon membrane. Shown are the time courses of the membrane potential (A) and the conductances for sodium and potassium ions (B)

The Na⁺ channel conducts Na⁺ 11 times better than K⁺. How is such selectivity achieved? A definitive answer to this question must await high-resolution structural Analysis of the channel. Nevertheless, electrophysiological studies on the relative permeability of the channel to various alkali metal and organic cations offer valuable clues. The dependence of permeability on ion size (Table 37.1) indicates that the channel is narrow: ions with a diameter exceeding 5 Å cannot pass through. However, conductance is governed by factors beyond mere size. For instance, methylamine (H₃CNH₃⁺) is nearly identical in size to hydrazine (H₂NNH₃⁺) and hydroxylamine (HONH₃⁺), yet it permeates the channel vastly less effectively. The reason likely lies in the fact that the methyl group of methylamine, unlike the amino group of hydrazine or the hydroxyl group of hydroxylamine, fails to form a Hydrogen bond with an oxygen atom lining the channel. Consequently, methylamine is blocked from passing. Another crucial finding has emerged: the conductance of the Na⁺ channel for all permeant cations drops significantly as the pH is lowered. In fact, the relative permeability profile mirrors an acid titration curve with a pK of 5.2, pointing to the presence of a negatively charged carboxylate ion within the functional Active Site of the channel. Thus, the selectivity of the Na⁺ channel for Na⁺ is conferred by a narrow, negatively charged region. The K⁺ ion, being larger than Na⁺, is virtually excluded from traversing this region (Fig. 37.3).

Table 37.1. Relative permeability of sodium and potassium channels in axon membranes

Fig. 37.3. The selectivity of the sodium channel for ions is determined in part by steric factors. Na⁺ and Li⁺ ions, complete with their Hydration shells, as well as hydroxylamine and hydrazine, fit the dimensions of the channel. In contrast, hydrated K⁺ is too bulky to pass through