Ion channels

Ion channels are proteins that form pores across the cell membrane and allow selective transfer of ions (charged species) in and out of the cell. Opening or closing of these channels is known as ‘gating’; this occurs as a result of the ion channel undergoing a change in shape. Gating is controlled either by transmitter substances or by the membrane potential (voltage-operated channels).

Some drugs modulate ion channel function directly by blocking the pore (e.g. the blocking action of local anaesthetics on sodium channels); others bind to a part of the ion channel protein to modify its action (e.g. anxiolytics acting on the GABA channel). Other drugs interact with ion channels indirectly via a G-protein and other intermediates.

Carrier molecules

Transfer of ions and molecules against their concentration gradients is facilitated by carrier molecules located in the cell membrane. There are two types of carrier molecule:

1 Receptors directly linked to ion channels

Receptors that are directly linked to ion channels (Fig. 1.3) are mainly involved in fast synaptic neurotransmission. A classic example of a receptor linked directly to an ion channel is the nicotinic acetylcholine receptor (nicAChR).

Fig. 1.3 General structure of the subunits of receptors directly linked to ion channels. (C, C-terminal; N, N-terminal.)

(Redrawn from Page et al. 2006.)

The nicAChRs possess several characteristics:

2 G-protein linked receptors

G-protein linked receptors (Fig. 1.4) are involved in relatively fast transduction. G-protein linked receptors are the predomínant receptor type in the body; muscarinic, ACh, adrenergic, dopamine, serotonin and opiate receptors are all examples of G-protein linked receptors.

Fig. 1.4 General structure of the subunits of receptors linked to G-proteins. (C, C-terminal; N, N-terminal.)

(Redrawn from Page et al. 2006.)

G-proteins

Figure 1.5 illustrates the mechanism of G-protein linked receptors:

• In resting state, the G-protein is unattached to the receptor and is a trimer consisting of α, β and γ subunits (Fig. 1.5A).

• The occupation of the receptor by an agonist produces a conformational change, causing its affinity for the trimer to increase. Subsequent association of the trimer with the receptor results in the dissociation of bound guanosine diphosphate (GDP) from the α subunit. Guanosine triphosphate (GTP) replaces GDP in the cleft thereby activating the G-protein and causing the α subunit to dissociate from the βγ dimer (Fig. 1.5B).

• α-GTP represents the active form of the G-protein (although this is not always the case: in the heart, potassium channels are activated by the βγ dimer and recent research has shown that the γ subunit alone may play a role in activation). This component diffuses in the plane of the membrane where it is free to interact with downstream effectors such as enzymes and ion channels. The βγ dimer remains associated with the membrane owing to its hydrophobicity (Fig. 1.5C).

• The cycle is completed when the α subunit, which has enzymic activity, hydrolyses the bound GTP to GDP. The GDP-bound α subunit dissociates from the effector and recombines with the βγ dimer (Fig. 1.5D).

Fig. 1.5 Mechanism of action of G-protein linked receptors. (α, β, γ, subunits of G-protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; G, guanosine; GDP, GTP, guanosine di- and triphosphate; p, phosphate.)

(Redrawn from Page et al. 2006.) Integrated Pharmacology, 3rd edition, Mosby.

This whole process results in an amplification effect because the binding of an agonist to the receptor can cause the activation of numerous G-proteins which in turn can each, via their association with the effector, produce many molecules of product.

Many types of G-protein exist. This is probably attributable to the variability of the α subunit. G_s and G_i/G_o cause stimulation and inhibition, respectively, of the target enzyme adenylyl cyclase. This explains why muscarinic ACh receptors (G_i/G_o linked) and β-adrenoreceptors (G_s linked) located in the heart produce opposite effects. The bacterial toxins cholera and pertussis can be used in order to determine which G-protein is involved in a particular situation. Each has enzymic action on a conjugation reaction with the α subunit, such that:

• Cholera affects G_s causing continued activation of adenylyl cyclase. This explains why infection with cholera toxin results in uncontrolled fluid secretion from the gastrointestinal tract.

• Pertussis affects G_i and G_o causing continued inactivation of adenylyl cyclase. This explains why infection with Bordetella pertussis causes a ‘whooping’ cough, characteristic of this infection, as the airways are constricted, and the larynx experiences muscular spasms.

Targets for G-proteins

G-proteins interact with either ion channels or secondary messengers. G-proteins may activate ion channels directly, e.g. muscarinic receptors in the heart are linked to potassium channels which open directly on interaction with the G-protein, causing a slowing down of the heart rate. Secondary messengers are a family of mediating chemicals that transduces the receptor activation in to a cellular response. These mediators can be targeted and three main secondary messenger systems exist as targets of G-proteins (Fig. 1.6).

Fig. 1.6 Second-messenger targets of G-proteins and their effects. (AA, arachidonic acid ; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; IP₃, inositol (1,4,5) triphosphate; PK, protein kinase.)

Adenylyl cyclase/cAMP system

Adenylyl cyclase catalyses the conversion of ATP to cyclic cAMP within cells. The cAMP produced in turn causes activation of certain protein kinases, enzymes that phosphorylate serine and threonine residues in various proteins, thereby producing either activation or inactivation of these proteins. A stimulatory example of this system can be observed in the activation of β₁-adrenergic receptors found in cardiac muscle. The activation of β₁-adrenergic receptors results in the activation of cAMP-dependent protein kinase A, which phosphorylates and opens voltage-operated calcium channels. This increases calcium levels in the cells and results in an increased rate and force of contraction. An inhibitory example of this system can be observed in activation of opioid receptors. The receptor linked to the ‘G_i’ protein inhibits adenylyl cyclase and reduces cAMP production.

Phospholipase C/inositol phosphate system

Activation of M₁, M₃, 5-HT₂, peptide and α₁-adrenoreceptors, via G_q, cause activation of phospholipase C, a membrane-bound enzyme, which increases the rate of degradation of phosphatidylinositol (4,5) bisphosphate into diacylglycerol (DAG) and inositol (1,4,5) triphosphate (IP₃). DAG and IP₃ act as second messengers. IP₃ binds to the membrane of the endoplasmic reticulum, opening calcium channels and increasing the concentration of calcium within the cell. Increased calcium levels may result in smooth muscle contraction, increased secretion from exocrine glands, increased hormone or transmitter release, or increased force and rate of contraction of the heart. DAG, which remains associated with the membrane owing to its hydrophobicity, causes protein kinase C to move from the cytosol to the membrane where DAG can regulate the activity of the latter. There are at least six types of protein kinase C, with over 50 targets including:

• Release of hormones and neurotransmitters

• Smooth muscle contraction

• Inflammation

• Ion transport

• Tumour promotion.

Guanylyl cyclase system

Guanylyl cyclase catalyses the conversion of GTP to cGMP. This cGMP goes on to cause activation of protein kinase G which in turn phosphorylates contractile proteins and ion channels. Transmembrane guanylyl cyclase activity is exhibited by the atrial natriuretic peptide receptor upon the binding of atrial natriuretic peptide. Cytoplasmic guanylyl cyclase activity is exhibited when bradykinin activates receptors on the membrane of endothelial cells to generate nitric oxide, which then acts as a second messenger to activate guanylyl cyclase within the cell.

3 Tyrosine kinase linked receptors

Tyrosine kinase linked receptors are involved in the regulation of growth and differentiation, and responses to metabolic signals. The response time of enzyme-initiated transduction is slow (minutes). Examples include the receptors for insulin, platelet-derived growth factor and epidermal growth factor.

Activation of tyrosine kinase receptors results in autophosphorylation of tyrosine residues leading to the activation of pathways involving protein kinases.

4 DNA linked receptors

DNA linked receptors are located intracellularly and so agonists must pass through the cell membrane in order to reach the receptor. The agonist binds to the receptor and this receptor–agonist complex is transported to the nucleus, aided by chaperone proteins. Once in the nucleus the complex can bind to specific DNA sequences and so alter the expression of specific genes. As a result, transcription of this specific gene to mRNA is increased or decreased and thus the amount of mRNA available for translation into a protein increases or decreases. The process is much slower than for other receptor–ligand interactions, and the effects usually last longer. Examples of molecules with DNA-linked receptors are corticosteroids, thyroid hormone, retinoic acid and vitamin D.

Agonists

Agonist (A) binds to the receptor (R) and the chemical energy released on binding induces a conformational change that sets off a chain of biochemical events within the cell, leading to a response (AR*). The equation for this is:

where: (1) affinity; (2) efficacy.

Partial agonists cannot bring about the same maximum response as full agonists, even if their affinity for the receptor is the same (Fig. 1.7).

Fig. 1.7 Comparison for a partial agonist and a full agonist showing (A) the dose–response curve and (B) the log dose–response curve.

(From Neal MJ 2009 Medical Pharmacology at a Glance, 6th edition. Wiley-Blackwell, with permission.)

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