(Goodman & Gilman, Chapter 2 -- pp. 34-6)

In any instance where there is a receptor, the interaction between that receptor and either its endogenous ligand or a drug designed to mimic the endogenous ligand will result in a chain of events that are unique for that receptor-ligand interaction.  The specific effects that result from the interaction depend upon the ligand (which may be a neurotransmitter, autocoid, or hormone), the receptor type or subtype, the location within the body, and the effector mechanism to which the receptor type/subtype is linked.  Recall that there are basically four (4) families of receptors.

Ion-Coupled Receptors
The classic example of an ion-coupled receptor is the nicotinic cholinergic receptor.  Interaction between acetylcholine (the endogenous neurotransmitter) and its specific binding site on the receptor causes a conformational change in the shape of the receptor.  This change in shape results in the opening of a pore or channel, allowing the influx of sodium ions.  Receptors exist that either open or close channels for sodium, calcium, potassium, and chloride ions.

Enzyme-Coupled Receptors
The second family of receptors is coupled directly with an enzyme that, upon interaction of the receptor with its ligand, becomes activated.  The resulting biochemical reaction is obviously dependent upon the enzyme to which the receptor is coupled.  Many of these receptor-enzymes are protein kinases that respond to peptide hormones.  Examples of receptors that are linked to enzymes include those for insulin, various growth factors, and some of the lymphokine receptors.  One example is the cGMP-coupled-receptor (Guanylyl cyclase/cyclic GMP or GC/cGMP).  This receptor's action is very similar to AC/cAMP described below except that guanosine monophosphate is formed rather than adenosine monophosphate.  In many instances, guanylyl cyclase is intrinsic to the receptor protein, so that the receptor is more properly classified as an enzyme-coupled receptor.  Another example is the enzyme tyrosine kinase, to which the insulin receptor is coupled.

G-Protein-Coupled Receptors
This is probably the largest family of receptors.  The receptors of this family are always long proteins that traverse the cellular membrane seven times.  For this reason, the family is often referred to as seven transmembrane receptors.  Muscarinic cholinergic, alpha and beta adrenergic, serotonergic, histaminergic,  and dopaminergic receptors may all be G-protein coupled (NOTE that this is the general rule and the receptor may differ slightly -- for instance one serotonin receptor subtype is coupled to an ion channel).  Receptor occupation will result in the activation of a second messenger system.  The specific second messenger is also dependent upon the receptor type and the location within the body (for instance the second messenger may be adenylyl cyclase in one area or phosphoinositide in another).  The response to receptor occupation may be excitatory or it may be inhibitory, depending upon both the second messenger and the physiologic effect of the second messenger.  This is often dependent upon where specifically in the body the receptor is located.  The G-proteins that act as second messengers which are most commonly encountered are summarised below.

G_s -- Adenylyl cyclase/cyclic AMP (AC/cAMP) -- receptor occupation results in the activation of the enzyme adenylyl cyclase (also referred to as adenyl cyclase or adenylate cyclase) which in turn causes the formation of cAMP.  The increase in intracellular cAMP is responsible for the physiologic action of ligand-receptor interaction, thus it acts as the second messenger, with the ligand being the first messenger.

G_q/11 -- Phosphoinositide/Diacyl glycerol (PI/DAG) -- receptor occupation by the endogenous ligand causes the activation of the membrane-bound enzyme phospholipase.  This, in turn, causes a cascade event utilising inositol, diacyl glycerol, and often various protein kinases which leads to the specific cellular response.  Often, influx of calcium also plays an important role in this receptor type.

G_i/o -- In addition to the specific second messengers, some G-protein coupled receptors may modulate ion channels.  NOTE that these receptors may or may not open or close specific channels.  The specific response is unique to the receptor and its location.  This family most often results in increased potassium efflux, decreased calcium influx, and decreased AC/cAMP activity/formation.

Nuclear Receptors -- This family of receptors binds with the ligand either in the cytoplasm of the cell or on the membrane of the nucleus of the cell.  Examples of hormones that act by this type of receptor include androgens, œstrogens, cortisone and aldosterone (hence, they are often called steroid-type receptors).  Receptor occupation results in the nuclear uptake of the hormone-receptor complex.  The physiologic effect elicited by receptor occupation results from protein synthesis that is prompted by interactions between the hormone-receptor complex and DNA within the nucleus.

Some definitions -- For the purposes of this class, the following definitions will be very important.  In the discipline of pharmacology, the terms mechanism of action, pharmacodynamics, and response are often used (sometimes interchangeably) to indicate how a drug acts and the effects it produces.  The following definitions are not the be-all, end-all definitions, but for this course, the distinctions will be important.

Mechanism of action -- refers to the actual interaction of a drug with some cellular component.  Example -- Nicotine will bind to the cholinergic nicotinic receptor.  Since it has both affinity and efficacy for that receptor it binds to it AND activates it.  Therefore, mechanistically, nicotine acts by binding to and activating the nicotinic cholinergic receptor, thus acting as a nicotinic agonist (some drugs by bind to a receptor and inhibit their activation, an antagonistic effect).

Pharmacodynamic Effect -- this is the immediate response to that receptor activation/inhibition or cellular response.  Using the same example, upon activation of the cholinergic receptor, a sodium channel is opened, causing influx of sodium into the cell, thus causing cellular depolarisation.  Thus the pharmacodynamic effect of nicotine is to cause cellular depolarisation via sodium influx.  

Physiologic Response -- this reflects the larger response that occurs when the receptors are activated and the cells are depolarised.  As an example, muscle will contract, so that one physiologic response to cholinergic nicotinic stimulation could be muscle contraction.

Therapeutic Response -- These are the desired goals of drug action.  As the course progresses, there will be many therapeutic responses (improved cardiac output, decreased peripheral resistance, lowering of blood glucose, et c.) that are either direct or indirect results of a drug's mechanism of action, pharmacodynamic effect, and physiologic response.

These concepts will be the basis for this course.  Extensions of these are also important and will provide the bases for discussions of clinical usefulness, side effects, and toxicities.

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