Editing Dopamine (section)

===Cellular effects===
{{Main|Dopamine receptor|TAAR1}}
{| class="wikitable" style="float:right; margin-left:10px; text-align:center;"
|+[[Biological target|Primary targets]] of dopamine in the human brain<ref name="DA IUPHAR">{{cite web |title=Dopamine: Biological activity |url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=940 |access-date=29 January 2016 |website=IUPHAR/BPS guide to pharmacology |publisher=International Union of Basic and Clinical Pharmacology |language=en-US}}</ref><ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction" – The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug and Alcohol Dependence | volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | pmc = 4724540 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = TAAR1 is a high-affinity receptor for METH/AMPH and DA }}</ref>
|-
! scope="col" | Family
! scope="col" | Receptor
! scope="col" | Gene
! scope="col" | Type
! scope="col" | Mechanism
|-
| rowspan=2 | [[D1-like receptor|D<sub>1</sub>-like]]
| [[Dopamine receptor D1|D<sub>1</sub>]]
| {{Gene|DRD1}}
| rowspan=2 | [[Gs alpha subunit|G<sub>s</sub>]]-coupled.
| rowspan=2 | Increase intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> by activating [[adenylate cyclase]].
|-
| [[Dopamine receptor D5|D<sub>5</sub>]]
| {{Gene|DRD5}}
|-
| rowspan=3 | [[D2-like receptor|D<sub>2</sub>-like]]
| [[Dopamine receptor D2|D<sub>2</sub>]]
| {{Gene|DRD2}}
| rowspan=3 | [[Gi alpha subunit|G<sub>i</sub>]]-coupled.
| rowspan=3 | Decrease intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> by inhibiting [[adenylate cyclase]].
|-
| [[Dopamine receptor D3|D<sub>3</sub>]]
| {{Gene|DRD3}}
|-
| [[Dopamine receptor D4|D<sub>4</sub>]]
| {{Gene|DRD4}}
|-
| [[Trace amine-associated receptor|TAAR]]
| [[TAAR1]]
| {{Gene|TAAR1}}
| [[Gs alpha subunit|G<sub>s</sub>]]-coupled.<br />[[Gq alpha subunit|G<sub>q</sub>]]-coupled.
| Increase intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> and intracellular calcium concentration.
|}

Dopamine exerts its effects by binding to and activating [[cell surface receptor]]s.<ref name=Seeman/> In humans, dopamine has a high [[binding affinity]] at [[dopamine receptor]]s and [[human trace amine-associated receptor 1]] (hTAAR1).<ref name="DA IUPHAR" /><ref name="Miller+Grandy 2016" /> In mammals, five subtypes of [[dopamine receptor]]s have been identified, labeled from D<sub>1</sub> to D<sub>5</sub>.<ref name=Seeman>{{cite book| title=The Dopamine Receptors |chapter=Chapter 1: Historical overview: Introduction to the dopamine receptors | vauthors = Seeman P | veditors = Neve K| publisher=Springer |year=2009 |isbn=978-1-60327-333-6 |pages=1–22}}</ref> All of them function as [[metabotropic receptor|metabotropic]], [[G protein-coupled receptor]]s, meaning that they exert their effects via a complex [[second messenger system]].<ref name=Romanelli>{{cite book| title=The Dopamine Receptors |chapter=Chapter 6: Dopamine receptor signalling: intracellular pathways to behavior | vauthors = Romanelli RJ, Williams JT, Neve KA | veditors = Neve KA| publisher = Springer | year = 2009 | isbn = 978-1-60327-333-6 | pages = 137–74}}</ref> These receptors can be divided into two families, known as [[D1-like receptor|D<sub>1</sub>-like]] and [[D2-like receptor|D<sub>2</sub>-like]].<ref name=Seeman/> For receptors located on neurons in the nervous system, the ultimate effect of D<sub>1</sub>-like activation (D<sub>1</sub> and D<sub>5</sub>) can be excitation (via opening of [[sodium channel]]s) or inhibition (via opening of [[potassium channel]]s); the ultimate effect of D<sub>2</sub>-like activation (D<sub>2</sub>, D<sub>3</sub>, and D<sub>4</sub>) is usually inhibition of the target neuron.<ref name=Romanelli/> Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory: its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to the second messenger [[Cyclic adenosine monophosphate|cAMP]].<ref name=Romanelli/> D<sub>1</sub> receptors are the most numerous dopamine receptors in the human nervous system; D<sub>2</sub> receptors are next; D<sub>3</sub>, D<sub>4</sub>, and D<sub>5</sub> receptors are present at significantly lower levels.<ref name=Romanelli/>

====Storage, release, and reuptake====
[[File:Dopaminergic synapse.svg|class=skin-invert-image|thumb|right|Dopamine processing in a synapse.  After release, dopamine can either be taken up again by the presynaptic terminal, or broken down by enzymes.<br />TH: [[tyrosine hydroxylase]]<br /> DOPA: [[L-DOPA]]<br /> DAT: [[dopamine transporter]]<br /> DDC: [[DOPA decarboxylase]]<br /> VMAT: [[vesicular monoamine transporter 2]]<br /> MAO: [[Monoamine oxidase]]<br /> COMT: [[Catechol-O-methyl transferase]]<br /> HVA: [[Homovanillic acid]]|alt=Cartoon diagram of a dopaminergic synapse, showing the synthetic and metabolic mechanisms as well as the things that can happen after release.]]
Inside the brain, dopamine functions as a neurotransmitter and [[neuromodulator]], and is controlled by a set of mechanisms common to all [[monoamine neurotransmitter]]s.<ref name=Seeman/> After synthesis, dopamine is transported from the [[cytosol]] into secretory vesicles, including [[synaptic vesicle]]s, small and [[large dense core vesicles]] by a [[solute carrier family|solute carrier]]—a [[vesicular monoamine transporter]], [[vesicular monoamine transporter 2|VMAT2]].<ref name=Eiden>{{cite journal | vauthors = Eiden LE, Schäfer MK, Weihe E, Schütz B | s2cid = 20764857 | title = The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 636–40 | date = February 2004 | pmid = 12827358 | doi = 10.1007/s00424-003-1100-5 }}</ref><ref>{{cite journal | vauthors = Westerink RH | title = Targeting exocytosis: ins and outs of the modulation of quantal dopamine release | journal = CNS & Neurological Disorders Drug Targets | volume = 5 | issue = 1 | pages = 57–77 | date = February 2006 | pmid = 16613554 | doi = 10.2174/187152706784111597 | hdl-access = free | hdl = 1874/11642 }}</ref> Dopamine is stored in these vesicles until it is ejected into the [[chemical synapse|synaptic cleft]]. In most cases, the release of dopamine occurs through a process called [[exocytosis]] which is caused by [[action potential]]s, but it can also be caused by the activity of an intracellular [[trace amine-associated receptor]], [[TAAR1]].<ref name="Miller+Grandy 2016" /> TAAR1 is a high-affinity receptor for dopamine, [[trace amine]]s, and certain [[substituted amphetamine]]s that is located along membranes in the intracellular milieu of the presynaptic cell;<ref name="Miller+Grandy 2016" /> activation of the receptor can regulate dopamine signaling by inducing dopamine [[reuptake inhibition]] and [[transporter reversal|efflux]] as well as by inhibiting neuronal firing through a diverse set of mechanisms.<ref name="Miller+Grandy 2016" /><ref name="Miller" />

Once in the synapse, dopamine binds to and activates dopamine receptors.<ref name="D2 Long and short" /> These can be [[chemical synapse|postsynaptic]] dopamine receptors, which are located on [[dendrite]]s (the postsynaptic neuron), or presynaptic [[autoreceptor]]s (e.g., the [[dopamine receptor D2#Isoforms|D<sub>2</sub>sh]] and presynaptic D<sub>3</sub> receptors), which are located on the membrane of an [[axon terminal]] (the presynaptic neuron).<ref name=Seeman/><ref name="D2 Long and short">{{cite journal | vauthors = Beaulieu JM, Gainetdinov RR | s2cid = 2545878 | title = The physiology, signaling, and pharmacology of dopamine receptors | journal = Pharmacological Reviews | volume = 63 | issue = 1 | pages = 182–217 | date = March 2011 | pmid = 21303898 | doi = 10.1124/pr.110.002642 }}</ref> After the postsynaptic neuron elicits an action potential, dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via [[reuptake]] mediated either by the [[dopamine transporter]] or by the [[plasma membrane monoamine transporter]].<ref name=Torres>{{cite journal | vauthors = Torres GE, Gainetdinov RR, Caron MG | s2cid = 21545649 | title = Plasma membrane monoamine transporters: structure, regulation and function | journal = Nature Reviews. Neuroscience | volume = 4 | issue = 1 | pages = 13–25 | date = January 2003 | pmid = 12511858 | doi = 10.1038/nrn1008 }}</ref> Once back in the cytosol, dopamine can either be broken down by a [[monoamine oxidase]] or repackaged into vesicles by VMAT2, making it available for future release.<ref name=Eiden/>

In the brain the level of extracellular dopamine is modulated by two mechanisms: [[Sensory receptor#Rate of adaptation|phasic and tonic transmission]].<ref name="Rice">{{cite journal | vauthors = Rice ME, Patel JC, Cragg SJ | title = Dopamine release in the basal ganglia | journal = Neuroscience | volume = 198 | pages = 112–37 | date = December 2011 | pmid = 21939738 | pmc = 3357127 | doi = 10.1016/j.neuroscience.2011.08.066 }}</ref> Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells.<ref name=Rice/> Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials.<ref name=Rice/> Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.<ref name=Rice/>