The mechanism of nicotinic receptor activation has been studied in great detail, taking advantage of three factors: (1) the receptor is present in extremely high concentration in the membranes of the electric organs of electric fish; (2) α-bungarotoxin, a component of certain snake venoms, binds tightly to the receptors and is readily labeled as a marker for isolation procedures; and (3) receptor activation results in easily measured electrical and ionic changes in the cells involved. The nicotinic receptor in muscle tissues (Figure 7–4B) is a pentamer of four types of glycoprotein subunits (one monomer occurs twice) with a total molecular weight of about 250,000. The neuronal nicotinic receptor consists of α and β subunits only (Table 7–1). Each subunit has four transmembrane segments. The nicotinic receptor has two agonist binding sites at the interfaces formed by the two α subunits and two adjacent subunits (β, γ, ε). Agonist binding to the receptor sites causes a conformational change in the protein (channel opening) that allows sodium and potassium ions to diffuse rapidly down their concentration gradients (calcium ions may also carry ––+˜°˛ACh ACh Vagus nerve varicosity Acetylcholine autoreceptor ACh M2R Sinoatrial nodal cell AC IK, ACh If ICa ATP cAMP PKA˝ATP Channel ˜˛°Gi/o
FIGURE 7–4 Muscarinic and nicotinic signaling. A: Muscarinic transmission to the sinoatrial node in heart. Acetylcholine (ACh) released from a varicosity of a postganglionic cholinergic axon interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, which causes hyperpolarization, and to inhibition of cAMP synthesis. Reduced cAMP shifts the voltage-dependent opening of pacemaker channels (If) to more negative potentials, and reduces the phosphorylation and availability of L-type Ca2+ channels (ICa). Released ACh also acts on an axonal muscarinic receptor (autoreceptor; see Figure 6–3) to cause inhibition of ACh release (autoinhibition). B: Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.
charge through the nicotinic receptor ion channel). Binding of an agonist molecule by one of the two receptor sites only modestly increases the probability of channel opening; simultaneous binding of agonist by both of the receptor sites greatly enhances opening probability. Nicotinic receptor activation causes depolarization of the nerve cell or neuromuscular end plate membrane. In skeletal muscle, the depolarization initiates an action potential that propagates across the muscle membrane and causes contraction (Figure 7–4B).
Prolonged agonist occupancy of the nicotinic receptor abolishes the effector response; that is, the postganglionic neuron stops firing (ganglionic effect), and the skeletal muscle cell relaxes (neuromuscular end plate effect). Furthermore, the continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane. Thus, a state of “depolarizing blockade” occurs initially during persistent agonist occupancy of the receptor. Continued agonist occupancy is associated with return of membrane voltage to the resting level. The receptor becomes desensitized to agonist, and this state is refractory to reversal by other agonists. As described in Chapter 27, this effect can be exploited to produce muscle paralysis.
B. Organ System Effects