Heterotrimeric G protein#alpha subunit

{{Main|G alpha subunit}}

File:GPCR cycle.jpg

Reconstitution experiments carried out in the early 1980s showed that purified G_α subunits can directly activate effector enzymes. The GTP form of the α subunit of transducin (G_t) activates the cyclic GMP phosphodiesterase from retinal rod outer segments,{{cite journal | vauthors = Fung BK, Hurley JB, Stryer L | title = Flow of information in the light-triggered cyclic nucleotide cascade of vision | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 1 | pages = 152–6 | date = January 1981 | pmid = 6264430 | pmc = 319009 | doi = 10.1073/pnas.78.1.152 | bibcode = 1981PNAS...78..152F | doi-access = free }} and the GTP form of the α subunit of the stimulatory G protein (G_s) activates hormone-sensitive adenylate cyclase.{{cite journal | vauthors = Cerione RA, Sibley DR, Codina J, Benovic JL, Winslow J, Neer EJ, Birnbaumer L, Caron MG, Lefkowitz RJ | title = Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit | journal = The Journal of Biological Chemistry | volume = 259 | issue = 16 | pages = 9979–82 | date = August 1984 | doi = 10.1016/S0021-9258(18)90913-0 | pmid = 6088509 | display-authors = etal | doi-access = free }}{{cite journal | vauthors = May DC, Ross EM, Gilman AG, Smigel MD | title = Reconstitution of catecholamine-stimulated adenylate cyclase activity using three purified proteins | journal = The Journal of Biological Chemistry | volume = 260 | issue = 29 | pages = 15829–33 | date = December 1985 | doi = 10.1016/S0021-9258(17)36333-0 | pmid = 2999139 | doi-access = free }} More than one type of G protein co-exist in the same tissue. For example, in adipose tissues, two different G-proteins with interchangeable beta-gamma complexes are used to activate or inhibit adenylyl cyclase. The alpha subunit of a stimulatory G protein activated by receptors for stimulatory hormones could stimulate adenylyl cyclase, which activates cAMP used for downstream signal cascades. While on the other hand, the alpha subunit of an inhibitory G protein activated by receptors of inhibitory hormones could inhibit adenylyl cyclase, which blocks downstream signal cascades.

G_α subunits consist of two domains, the GTPase domain, and the alpha-helical domain.

There exist at least 20 different G_α subunits, which are separated into four main groups. This nomenclature is based on their sequence homologies:{{cite journal | vauthors = Strathmann MP, Simon MI | title = G alpha 12 and G alpha 13 subunits define a fourth class of G protein alpha subunits | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 13 | pages = 5582–6 | date = July 1991 | pmid = 1905812 | pmc = 51921 | doi = 10.1073/pnas.88.13.5582 | bibcode = 1991PNAS...88.5582S | doi-access = free }}

{{Main|G beta-gamma complex}}

The β and γ subunits are closely bound to one another and are referred to as the G beta-gamma complex. Both beta and gamma subunits have different isoforms, and some combination of isoforms result in dimerization while other combinations do not. For example, beta1 binds both gamma subunits while beta3 binds neither.{{cite journal | vauthors = Schmidt CJ, Thomas TC, Levine MA, Neer EJ | title = Specificity of G protein beta and gamma subunit interactions | journal = The Journal of Biological Chemistry | volume = 267 | issue = 20 | pages = 13807–10 | date = July 1992 | doi = 10.1016/S0021-9258(19)49638-5 | pmid = 1629181 | url = http://www.jbc.org/content/267/20/13807 | doi-access = free }} Upon activation of the GPCR, the G_βγ complex is released from the G_α subunit after its GDP-GTP exchange.

The free G_βγ complex can act as a signaling molecule itself, by activating other second messengers or by gating ion channels directly.

For example, the G_βγ complex, when bound to histamine receptors, can activate phospholipase A₂. G_βγ complexes bound to muscarinic acetylcholine receptors, on the other hand, directly open G protein-coupled inward rectifying potassium channels (GIRKs).{{cite journal | vauthors = Gulati S, Jin H, Masuho I, Orban T, Cai Y, Pardon E, Martemyanov KA, Kiser PD, Stewart PL, Ford CP, Steyaert J, Palczewski K | title = Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor | journal = Nature Communications | volume = 9 | issue = 1 | pages = 1996 | year = 2018 | pmid = 29777099 | doi = 10.1038/s41467-018-04432-0 | pmc = 5959942 | bibcode = 2018NatCo...9.1996G }} When acetylcholine is the extracellular ligand in the pathway, the heart cell hyperpolarizes normally to decrease heart muscle contraction. When substances such as muscarine act as ligands, the dangerous amount of hyperpolarization leads to hallucination. Therefore, proper functioning of G_βγ plays a key role in our physiological well-being. The last function is activating L-type calcium channels, as in H₃ receptor pharmacology.

Heterotrimeric G-protein signaling in plants deviates from the metazoan model at various levels. For example, the presence of extra-Large G alpha, loss of G alpha and Regulator of G-protein signaling (RGS) in many plant lineages.{{cite journal |last1=Mohanasundaram |first1=Boominathan |last2=Dodds |first2=Audrey |last3=Kukshal |first3=Vandna |last4=Jez |first4=Joseph M |last5=Pandey |first5=Sona |title=Distribution and the evolutionary history of G-protein components in plant and algal lineages |journal=Plant Physiology |date=4 April 2022 |volume=189 |issue=3 |pages=1519–1535 |doi=10.1093/plphys/kiac153 | pmid=35377452 |pmc=9237705 }} In addition, the G-proteins are not essential for the survival in dicotyledonous plants, while they are essential for the survival of monocotyledonous plants.

{{Reflist|32em}}

• {{MeshName|Heterotrimeric+G-Proteins}}
• {{EC number|3.6.5.1}}

{{Intracellular signaling peptides and proteins}}

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Category:Peripheral membrane proteins

Category:EC 3.6.5