of 3h-noradrenaline was severely impaired after sympathectomy, indicating that it occurred mainly into sympathetic nerve terminals. in support of this, axelrod and georg hertting (born 1925) showed that freshly incorporated 3h-noradrenaline was re-released from the cat spleen when the sympathetic nerves were stimulated. a few years later, leslie iversen (born 1937) in cambridge found that other cells also took up catecholamines. he called uptake into noradrenergic neurons, which were cocaine-sensitive, uptake1 and uptake into other cells, which were cocaine-resistant, uptake2. with the reserpine-sensitive uptake from the cytoplasm into the storage vesicles there were thus three catecholamine membrane passage mechanisms. iversen's book of 1967 “the uptake and storage of noradrenaline in sympathetic nerves” was successful, showing the fascination of the field and its rich pharmacology. with the advent of molecular genetics, the three transport mechanisms have been traced to the proteins and their genes since 1990. they now consist of the plasma membrane noradrenaline transporter (nat or net), the classical uptake1, and the analogous dopamine transporter (dat); the plasma membrane extraneuronal monoamine transporter or organic cation transporter 3 (emt or slc22a3), iversen's uptake2; and the vesicular monoamine transporter (vmat) with two isoforms. transporters and intracellular enzymes such as monoamine oxidase operating in series constitute what the pharmacologist ullrich trendelenburg at the university of würzburg called metabolizing systems. receptors adrenaline reversal after henry hallett dale (1906). an ergot extract was injected between left-hand and right-hand tracings. presynaptic α2-autoreceptor and postsynaptic adrenoceptors of a noradrenergic axon terminal. amine receptor branch of the family tree of g protein-coupled receptors. the β2-adrenoceptor (blue) coupling to the heterotrimeric g protein gs (red, yellow, green) after binding of an agonist. research on the catecholamines was interwoven with research on their receptors. in 1904, dale became head of the wellcome physiological research laboratory in london and started research on ergot extracts. the relevance of his communication in 1906 ″on some physiological actions of ergot″ lies less in the effects of the extracts given alone than in their interaction with adrenaline: they reversed the normal pressor effect of adrenaline to a depressor effect and the normal contraction effect on the early-pregnant cat's uterus to relaxation: adrenaline reversal. the pressor and uterine contraction effects of pituitary extracts, in contrast, remained unchanged, as did the effects of adrenaline on the heart and effects of parasympathetic nerve stimulation. dale clearly saw the specificity of the ″paralytic″ (antagonist) effect of ergot for ″the so-called myoneural junctions connected with the true sympathetic or thoracic-lumbar division of the autonomic nervous system″ – the adrenoceptors. he also saw its specificity for the ″myoneural junctions″ mediating smooth muscle contraction as opposed to those mediating smooth muscle relaxation. but there he stopped. he did not conceive any close relationship between the smooth muscle-inhibitory and the cardiac sites of action of catecholamines. catecholamine receptors persisted in this wavering state for more than forty years. additional blocking agents were found such as tolazoline in switzerland and phenoxybenzamine in the united states, but like the ergot alkaloids they blocked only the smooth muscle excitatory receptors. additional agonists also were synthesized. outstanding among them became isoprenaline, n-isopropyl-noradrenaline, of boehringer ingelheim, studied pharmacologically along with adrenaline and other n-substituted noradrenaline derivatives by richard rössler (1897–1945) and heribert konzett (1912–2004) in vienna. the viennese pharmacologists used their own konzett-rössler test to examine bronchodilation. intravenous injection of pilocarpine to induce bronchospasm was followed by intravenous injection of the agonists. “arrangement of all amines according to their bronchodilator effect yields a series from the most potent, isopropyl-adrenaline, via the approximately equipotent bodies adrenaline, propyl-adrenaline and butyl-adrenaline, to the weakly active isobutyl-adrenaline.” isoprenaline also exerted marked positive chronotropic and inotropic effects. boehringer introduced it for use in asthma in 1940. after the war it became available to germany's former enemies and over the years was traded under about 50 names. in addition to this therapeutic success it was one of the agonists with which raymond p. ahlquist solved the ″myoneural junction″ riddle. “by virtue of this property the reputation of the substance spread all over the world and it became a tool for many investigations on different aspects of pharmacology and therapeutics.” the story had a dark side: overdosage caused numerous deaths due to cardiac side effects, an estimated three thousands in the united kingdom alone. ahlquist was head of the department of pharmacology of the university of georgia school of medicine, now georgia regents university. in 1948 he saw what had escaped dale in 1906. “the adrenotropic receptors have been considered to be of two classes, those whose action results in excitation and those whose action results in inhibition of the effector cells. experiments described in this paper indicate that although there are two kinds of adrenotropic receptors they cannot be classified simply as excitatory or inhibitory since each kind of receptor may have either action depending on where it is found.” ahlquist chose six agonists, including adrenaline, noradrenaline, α-methylnoradrenaline and isoprenaline, and examined their effects on several organs. he found that the six substances possessed two – and only two – rank orders of potency in these organs. for example, the rank order of potency was ″adrenaline > noradrenaline > α-methylnoradrenaline > isoprenaline″ in promoting contraction of blood vessels, but ″isoprenaline > adrenaline > α-methylnoradrenaline > noradrenaline″ in stimulating the heart. the receptor with the first rank order (for example for blood vessel contraction) he called alpha adrenotropic receptor (now α-adrenoceptor or α-adrenergic receptor), while the receptor with the second rank order (for instance for stimulation of the heart, but also for bronchodilation) he called beta adrenotropic receptor (now β-adrenoceptor or β-adrenergic receptor). ″this concept of two fundamental types of receptors is directly opposed to the concept of two mediator substances (sympathin e and sympathin i) as propounded by cannon and rosenblueth and now widely quoted as ‘law’ of physiology. ... there is only one adrenergic neuro-hormone, or sympathin, and that sympathin is identical with epinephrine.” the haze surrounding the receptors was thus blown away. yet, perhaps because ahlquist dismissed cannon and rosenblueth rather harshly, his manuscript was rejected by the journal of pharmacology and experimental therapeutics and only in a second submission accepted by the american journal of physiology. in retrospect, although ahlquist was right in his ″one transmitter – two receptors″ postulate, he erred in the identification of the transmitter with adrenaline. there is an additional qualification. for many responses to sympathetic nerve stimulation, the atp co-stored with noradrenaline ((see above)) is a cotransmitter. it acts through purinoceptors. lastly, ahlquist failed to adduce the selectivity of all antagonists known at his time for the α-adrenoceptor as an additional argument. the α,β-terminology initially was slow to spread. this changed with two publications in 1958. in the first, from lilly research laboratories, dichloroisoprenaline selectively blocked some smooth muscle inhibitory effects of adrenaline and isoprenaline; in the second, it blocked cardiac excitatory effects of adrenaline and isoprenaline as well. in the first, which does not mention ahlquist, dichloroisoprenaline blocked ″certain adrenergic inhibitory receptor sites″; but in the second the results ″support the postulate of ahlquist (1948) that the adrenotropic inhibitory receptors and the cardiac chronotropic and inotropic adrenergic receptors are functionally identical, i.e., that both are beta type receptors. … it is suggested that this terminology be extended to the realm of adrenergic blocking drugs, e.g., that blocking drugs be designated according to the receptor for which they have the greatest affinity, as either alpha or beta adrenergic blocking drugs.” dichloroisoprenaline was the first beta blocker; it retains some intrinsic activity. pronethalol followed in 1962 and propranolol in 1964, both invented by james black and his colleagues at imperial chemical industries pharmaceuticals in england. in 1967, β-adrenoceptors were subdivided into β1 and β2, and a third β type began to be suspected in the late 1970s, above all in adipocytes. after premonitions for example in the work of the portuguese pharmacologist serafim guimarães, α-adrenoceptor subclassification came in 1971 with the discovery of the self-regulation of noradrenaline release through α-adrenoceptors on noradrenergic synaptic terminals, presynaptic α-autoreceptors. their existence was initially combated but is now established, for example by the demonstration of their messenger rna in noradrenergic neurons. they differed from α-receptors on effector cells and in 1974 became the prototype α2-receptors, the long-known smooth muscle contraction-mediating receptors becoming α1. even before dopamine was identified as the third catecholamine transmitter, blaschko suspected it might possess receptors of its own, since peter holtz and his group in 1942 had found that small doses of dopamine lowered the blood pressure of rabbits and guinea pigs, whereas adrenaline always increased the blood pressure. holtz erred in his interpretation, but blaschko had ″no doubt that his observations are of the greatest historical importance, as the first indication of an action of dopamine that characteristically and specifically differs from those of the two other catecholamines″. a re-investigation of the blood pressure-lowering effect in dogs in 1964 proposed ″specific dopamine receptors for dilation″, and at the same time evidence for dopamine receptors distinct from α- and β-adrenoceptors accrued from other experimental approaches. in 1986, the first gene coding for a catecholamine receptor, the β2-adrenoceptor from hamster lung, was cloned by a group of sixteen scientists, among them robert lefkowitz and brian kobilka of duke university in durham, north carolina. genes for all mammalian catecholamine receptors have now been cloned, for the nine adrenoceptors α1a, α1b, α1d, α2a, α2b, α2c, β1, β2 and β3 and the five dopamine receptors d1, d2, d3, d4 and d5. their fine structure, without agonist or agonist-activated, is being studied at high resolution. earl wilbur sutherland won the 1971 nobel prize in physiology or medicine ″for his discoveries concerning the mechanisms of the action of hormones″, in particular the discovery of cyclic adenosine monophosphate as second messenger in the action of catecholamines at β-adrenoceptors and of glucagon at glucagon receptors, which led on to the discovery of heterotrimeric g proteins. in 1988 james black was one of three winners of the nobel prize in physiology or medicine ″for their discoveries of important principles for drug treatment″, black's ″important principles″ being the blockade of β-adrenoceptors and of histamine h2 receptors. in 2012, robert lefkowitz and brian kobilka shared the nobel prize in chemistry ″for studies of g-protein-coupled receptors″.