The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.
Many cells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system (SNS). The SNS is responsible for the fight-or-flight response, which is triggered by experiences such as exercise or fear-causing situations. This response dilates pupils, increases heart rate, mobilizes energy, and diverts blood flow from non-essential organs to skeletal muscle. These effects together tend to increase physical performance momentarily.
This line of experiments were developed by several groups, including DT Marsh and colleagues, who in February 1948 showed that a series of compounds structurally related to adrenaline could also show either contracting or relaxing effects, depending on whether or not other toxins were present. This again supported the argument that the muscles had two different mechanisms by which they could respond to the same compound. In June of that year, Raymond Ahlquist, Professor of Pharmacology at Medical College of Georgia, published a paper concerning adrenergic nervous transmission. In it, he explicitly named the different responses as due to what he called α receptors and β receptors, and that the only sympathetic transmitter was adrenaline. While the latter conclusion was subsequently shown to be incorrect (it is now known to be noradrenaline), his receptor nomenclature and concept of two different types of detector mechanisms for a single neurotransmitter, remains. In 1954, he was able to incorporate his findings in a textbook, Drill's Pharmacology in Medicine, and thereby promulgate the role played by α and β receptor sites in the adrenaline/noradrenaline cellular mechanism. These concepts would revolutionise advances in pharmacotherapeutic research, allowing the selective design of specific molecules to target medical ailments rather than rely upon traditional research into the efficacy of pre-existing herbal medicines.
The mechanism of adrenoreceptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenoreceptors. α1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.alt=]]
Epinephrine (adrenaline) reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated at pharmacologic doses, they override the vasodilation mediated by β-adrenoreceptors because there are more peripheral α1 receptors than β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. However, the opposite is true in the coronary arteries, where β2 response is greater than that of α1, resulting in overall dilation with increased sympathetic stimulation. At lower levels of circulating epinephrine (physiologic epinephrine secretion), β-adrenoreceptor stimulation dominates since epinephrine has a higher affinity for the β2 adrenoreceptor than the α1 adrenoreceptor, producing vasodilation followed by decrease of peripheral vascular resistance.
α1-adrenoreceptors are members of the Gq protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell. This triggers all other effects, including a prominent slow after depolarizing current (sADP) in neurons.
Actions of the α1 receptor mainly involve smooth muscle contraction. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney (renal artery) and brain. Other areas of smooth muscle contraction are:
The α2 receptor couples to the Gi/o protein. It is a presynaptic receptor, causing negative feedback on, for example, norepinephrine (NE). When NE is released into the synapse, it feeds back on the α2 receptor, causing less NE release from the presynaptic neuron. This decreases the effect of NE. There are also α2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.
Beta-1 receptors, along with beta-2, alpha-1, and alpha-2 receptors, are adrenergic receptors primarily responsible for signaling in the sympathetic nervous system. Beta-agonists bind to the beta receptors on various tissues throughout the body. Beta-1 receptors are predominantly found in three locations: the heart, the kidney, and the fat cells.
Targeted activation of the beta-1 receptor in the heart increases sinoatrial (SA) nodal, atrioventricular (AV) nodal, and ventricular muscular firing, thus increasing heart rate and contractility. With these two increased values, the stroke volume and cardiac output will also increase. This effect clearly shows in the cardiac output equation. Cardiac output equals the product of stroke volume and heart rate. As either stroke volume or heart rate increase, both of which will increase with targeted activation of the beta-1 receptor, cardiac output will increase, thus increasing perfusion to tissues throughout the body.
In the kidney, smooth muscle cells in the juxtaglomerular apparatus contract and release renin. This cascading effect will eventually increase blood volume through the actions of angiotensin II and aldosterone. In the adipocyte, the beta-1 receptor is targeted to upregulate lipolysis.
Various hormones may target the adrenoreceptors with different affinities. In this article, we will focus on the beta receptors, in particular, beta-1 adrenergic receptors. The chemicals epinephrine, dopamine, and isoproterenol target beta-1 and beta-2 receptors almost equally. Norepinephrine and dobutamine target beta-1 to a greater degree than beta-2.
The Gs subunit of the beta-1 adrenoreceptor upon activation upregulates adenylyl cyclase which converts ATP to cAMP. With the increased presence of cAMP, cAMP-dependent protein kinase A (PKA) phosphorylates calcium channels, thus increasing cellular calcium influx. Increased concentrations of intracellular calcium increase inotropy in the heart through calcium exchange in the sarcoplasmic reticulum. PKA also phosphorylates myosin light chains which lead to contractility in smooth muscle cells.
Day-to-day maintenance of blood pressure is accomplished with the constant opposition of the sympathetic and parasympathetic systems. Baroreceptors, located in the carotid sinus near the bifurcation of the common carotid artery, are stretch receptors that will sense any deviation from the set point (about 100 mm Hg) with decreased stretch on the receptor. The baroreceptors innervated by the herring nerve decrease parasympathetic outflow to the heart through cranial nerve X, the vagus nerve. With decreased parasympathetic outflow, the sympathetic nervous system runs less opposed, increasing heart rate, contractility, and stroke volume through the function of the beta-1 receptor. Through a similar mechanism, decreased renal perfusion causes the release of renin from the juxtaglomerular apparatus. Through a cascading effect, aldosterone is released, and blood volume increases through sodium retention.
Beta-blockers, like propranolol (nonselective, beta-1 and beta-2 receptor antagonists) and atenolol and landiolol (cardioselective and have very little affinity for the beta-2 receptor), are widely used for medical conditions including hypertension, arrhythmias, heart failure, chest pain, myocardial infarctions, migraines, and anxiety. By blocking the normal function of the receptor, there is a decrease in the binding of epinephrine and norepinephrine at the targeting the receptor. Blocking the receptor can be thought of as producing the opposite effect. Thus, the heart will generally beat more slowly and with less force. In turn, lowering blood pressure.
Illicit drug use is of particular note when talking about the beta-1 receptor. Cocaine increases the plasma concentrations of catecholamines including epinephrine and norepinephrine by inhibition of peripheral re-uptake and central sympathetic system stimulation. Increased levels of these catecholamines potentiate activation of the beta-1 receptor and thus lead to increased heart rate. In some patients, and in overdose, these increased levels can contribute to the onset of ventricular fibrillation (V-fib). With the rapid onset of cocaine effects, use of this drug can quickly become a medical emergency. Although increases in beta activation can precipitate an arrhythmia, beta-blocking agents are not recommended. Instead, treatment with alpha-blocking agents to prevent hypertension and malignant arrhythmias is the recommended therapeutic course.
The beta 1 receptor is vital for the normal physiological function of the sympathetic nervous system. Through various cellular signaling mechanisms, hormones and medications activate the beta-1 receptor. Targeted activation of the beta-1 receptor increases heart rate, renin release, and lipolysis. From day-to-day maintenance of blood pressure to manipulation of the receptor by recreational substances like cocaine and pharmacologic therapy including agonists like isoproterenol and antagonists like propranolol, the beta-1 receptor is essential to everyday clinical medicine. 59ce067264