Ca /calmodulin-dependent kinase

PKA and PKC are, however, not the only kinases to regulate TRPVl. The Ca /calmodulin-dependent kinase II (CaMKII) sensitizes TRPVl by phosphorylation [57, 58], as does phophatidylinositol 3-kinase (PI3K) via its downstream target AKT [59]. This latter finding links TRPVl to the ERK (extracellular signal-regulated protein kinase) pathway. The non-receptor tyrosine kinase Src likewise potentiates capsaicin-induced currents [60]. 

Cells can choose between several phosphorylation cascades, to cope with a multitude of extra- and intracellular signals. Cells have kinases which respond to second messengers, such as PKA, PKC and Ca -calmodulin-dependent kinases. Each of these kinases can establish a separate phosphorylation cascade. 

Wilmarth KR, Viana ME, Abou-Donia MB. 1993. Carbon disulfide inhalation increases Ca+/calmodulin-dependent kinase phosphorylation of cytoskeletal proteins in the rat central nervous system. Brain Research 628 293-300. 

Depolarization of the nerve terminal activates tyrosine hydroxylase. Depolarization also activates a number of protein kinases (including protein kinase C, protein kinase A [the cAMP-dependent protein kinase] and CAM kinases [Ca -calmodulin-dependent kinases]) that phosphorylate tyrosine hydroxylase. These activation steps result in an enzyme that binds BH4 more tightly, making it less sensitive to end-product inhibition. 

Scott-Woo GC, Sutherland C, Walsh MP (1990) Kinase activity associated with caldes-mon is Ca /calmodulin-dependent kinase II. Biochem J 268 367-370 Seguchi H, Nishimura J, Toyofuku K, Kobayashi S, Kumazawa J, Kanaide H (1996) The mechanism of relaxation induced by atrial natriuretic peptide in the porcine renal artery. British J Pharmacol 118 343-351... 

Welsby PJ, Wang H, Wolfe JT, Colbran RJ, Johnson ML, Barrett PQ. A mechanism for the direct regulation of T-type calcium channels by Ca /calmodulin-dependent kinase II. J Neurosci 2003 23(31) 10116-21. 

So far, it has been established from in vitro studies that the enzyme undergoes phosphorylation, a process that changes the conformation of the enzyme protein and leads to an increase in its activity. This involves Ca +/calmodulin-dependent protein kinase II and cAMP-dependent protein kinase which suggests a role for both intracellular Ca + and enzyme phosphorylation in the activation of tryptophan hydroxylase. Indeed, enzyme purified from brain tissue innervated by rostrally projecting 5-HT neurons, that have been stimulated previously in vivo, has a higher activity than that derived from unstimulated tissue but this increase rests on the presence of Ca + in the incubation medium. Also, when incubated under conditions which are appropriate for phosphorylation, the of tryptophan hydroxylase for its co-factor and substrate is reduced whereas its Fmax is increased unless the enzyme is purified from neurons that have been stimulated in vivo, suggesting that the neuronal depolarisation in vivo has already caused phosphorylation of the enzyme. This is supported by evidence that the enzyme activation caused by neuronal depolarisation is blocked by a Ca +/calmodulin protein kinase inhibitor. However, whereas depolarisation... 

Inositol triphosphate is water soluble and therefore diffuses into the cytoplasm, where it mobilizes calcium from its stores in microsomes or the endoplasmic reticulum. The Ca ions then activate Ca-dependent kinases (like troponin C in muscle) directly or bind to the ubiquitous Ca-binding protein calmodulin, which activates calmodulin-dependent kinases. These kinases, in turn, phosphorylate cell-specific enzymes. 

An example for the reversible association of activator proteins with an enzyme is the Ca -calmodulin dependent enzymes. Calmodulin is a Ca -binding protein which can activate target enzymes, e.g. phosphorylase kinase (see 6.7.1 and 7.4) in its Ca -boimd form. Another example for activating proteins is the cyclins (see chapter 14). The cyc-lins are activators of protein kinases that regulate the cell cycle. 

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